EP2063889A2 - Spiropiperidine beta-secretase inhibitors for the treatment of alzheimer's disease - Google Patents

Spiropiperidine beta-secretase inhibitors for the treatment of alzheimer's disease

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Publication number
EP2063889A2
EP2063889A2 EP07811660A EP07811660A EP2063889A2 EP 2063889 A2 EP2063889 A2 EP 2063889A2 EP 07811660 A EP07811660 A EP 07811660A EP 07811660 A EP07811660 A EP 07811660A EP 2063889 A2 EP2063889 A2 EP 2063889A2
Authority
EP
European Patent Office
Prior art keywords
methyl
triazaspiro
fluorophenyl
decane
dione
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07811660A
Other languages
German (de)
French (fr)
Other versions
EP2063889A4 (en
Inventor
Melissa S. Egbertson
Shaun R. Stauffer
Craig A. Coburn
James C. Barrow
Wenjin Yang
Wanli Lu
Bruce Fahr
Lou Anne Neilson
Jenny M. Wai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme LLC
Viracta Therapeutics Inc
Original Assignee
Merck and Co Inc
Sunesis Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck and Co Inc, Sunesis Pharmaceuticals Inc filed Critical Merck and Co Inc
Publication of EP2063889A2 publication Critical patent/EP2063889A2/en
Publication of EP2063889A4 publication Critical patent/EP2063889A4/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • the invention is directed to hydantoin, cyclic urea and cyclic carbamate spiropiperidine compounds which are useful as inhibitors of the beta secretase enzyme, and are useful in the treatment of diseases in which the beta secretase enzyme is involved, such as Alzheimer's Disease.
  • Alzheimer's disease is the most common cause of dementia in the elderly and is characterized by a decline in cognitive function. Alzheimer's Disease typically progresses slowly and results in symptoms such as memory loss and disorientation.
  • Existing treatments for Alzheimer's Disease such as acetylcholinesterase inhibitors, address the symptoms of Alzheimer's Disease but do not target the underlying causes of the disease.
  • the pathology of Alzheimer's disease is characterized by the deposition of amyloid in the brain in the form of extra-cellular plaques and intra-cellular neurofibrillary tangles.
  • the rate of amyloid accumulation is a combination of the rates of formation, aggregation and egress from the brain. It is generally accepted that the main constituent of amyloid plaques is the 4kD amyloid protein ( ⁇ A4, also referred to as A ⁇ , ⁇ -protein and ⁇ AP) which is a proteolytic product of a precursor protein of much larger size.
  • the amyloid precursor protein (APP or A ⁇ PP) has a receptor-like structure with a large ectodomain, a membrane spanning region and a short cytoplasmic tail.
  • the A ⁇ domain encompasses parts of both extra-cellular and transmembrane domains of APP, thus its release implies the existence of two distinct proteolytic events to generate its NH 2 - and COOH-termini.
  • APP S soluble, COOH-truncated forms of APP
  • Proteases that release APP and its fragments from the membrane are termed "secretases.”
  • Most APP 5 is released by a putative ⁇ - secretase which cleaves within the A ⁇ protein to release ⁇ -APP s and precludes the release of intact A ⁇ .
  • a minor portion of APP S is released by a ⁇ -secretase (" ⁇ -secretase”), which cleaves near the NH 2 -terminus of APP and produces COOH-terminal fragments (CTFs) which contain the whole A ⁇ domain.
  • ⁇ -secretase ⁇ -secretase
  • BACE amyloid precursor protein-cleaving enzyme
  • the compounds of the present invention are useful for treating Alzheimer's disease by inhibiting the activity of ⁇ -secretase or BACE, thus preventing the formation of insoluble A ⁇ and arresting the production of A ⁇ .
  • the present invention is directed to spiropiperidine compounds represented by general formula (I)
  • the invention is also directed to pharmaceutical compositions which include a therapeutically effective amount of a compound of formula (I), or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
  • the invention is also directed to methods of treating mammals for diseases in which the ⁇ -secretase enzyme is involved, such as Alzheimer's disease, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.
  • the present invention is directed to hydantoin, cyclic carbamate and urea spiropiperidine compounds represented by general formula (I)
  • X is selected from the group consisting of (I) N-RA
  • R2 is selected from the group consisting of (1) hydrogen, (2) -Ci_io alkyl, (3) -C2-IO alkenyl, (4) -C2-10 alkynyl,
  • (6) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen,
  • heteroaryl wherein said alkyl, cycloalkyl, heterocyclic group, alkenyl, alkynyl, aryl or heteroaryl R2 moiety is optionally substituted with one or more
  • Q is -Ci _e alkylene, wherein said alkylene is optionally substituted with one or more:
  • R 3 is selected from the group consisting of (1) hydrogen, (2) -CLIO alkyl, (3) -C2-IO alkenyl, (4) -C2-10 alkynyl,
  • heteroaryl wherein said alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl or aryl or heteroaryl R3 moiety is optionally substituted with one or more
  • heterocyclic wherein said heterocyclic group has from 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen, sulfur and oxygen, (D aryl, (k) heteroaryl, (1) -NR6R6' 5 and said alkyl, cycloalkyl, aryl and heteroaryl moiety is optionally substituted with one or more
  • R6 and R6' are selected from the group consisting of (1) hydrogen, (2) -Ci_ 6 alkyl, (3) -C3-7 cycloalkyl,
  • aryl or heteroaryl R5 moiety is optionally substituted with one or more
  • X is NR5, wherein R5 is preferably hydrogen.
  • R5 is selected from the group consisting of optionally substituted
  • R2 is phenyl, wherein the phenyl is optionally substituted with one or more (i) halo, (ii) -OH, (Ui) -CN, (iv) - Ci-io alkyl, and (v) phenyl optionally substituted with (A) halo, (BhOH, (C) -CN, (D) -Ci- 6 alkyl, (E) -OCi -6 alkyl, (F) -SO2Ci.3 alkyl, (H) -NR5SO2Ci_3alkyl, (I) -CO 2 RS,
  • Q is Ci .3 alkylene, most preferably -CH 2 -, and R3 is phenyl, wherein the phenyl is optionally substituted with one or more
  • R4 is— Cl -6 alkyl, most preferably methyl or ethyl.
  • X, Q, R.2, R ⁇ and R4 are as defined above, and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.
  • X is NR.5, and preferably R.5 is hydrogen.
  • R5 is selected from the group consisting of optionally substituted
  • R.2 is phenyl, wherein the phenyl is optionally substituted with one or more (i) halo, (U) -OH 5
  • phenyl optionally substituted with (A) halo, (B)-OH, (C) -CN, (D) -Ci_ 6 alkyl, (E) -OCi-6 alkyl, (F) - SO 2 CL 3 alkyl,
  • R4 is Cl -6 alkyl, most preferably methyl or ethyl.
  • Q is Ci_3 alkylene, most preferably — CH2— , and R3 is phenyl, wherein the phenyl is optionally substituted with one or more
  • R4 is CI_6 alkyl, most preferably methyl or ethyl.
  • R ⁇ is selected from the group consisting of
  • Q is Cl .3 alkyl ene, most preferably -CH2—
  • R 3 is phenyl, wherein the phenyl is optionally substituted with one or more
  • R4 is Ci_6 alkyl, most preferably methyl or ethyl.
  • the invention is directed to the following exemplary compounds of the invention: l-(3-fluorophenyl)-8-[(2'-methylbiphenyl-3-yl)methyl]-l,3,8-triazaspiro[4.5]decane-2 ? 4-dione; ⁇ -fluoro-l'-tS ⁇ S-isopropoxybenzy ⁇ -l ⁇ -dioxo-ljS ⁇ -triazaspiro ⁇ .SJdec-l-yl]- ⁇ - trimethylbiphenyl-4-sulfonamide;
  • the invention is also directed to methods of treating a patient (preferably a human) for diseases in which the ⁇ -secretase enzyme is involved, such as Alzheimer's disease, by administering a therapeutically effective amount of a spiropiperidine compound of any of the embodiments of formula (I), (IT), (HI), or (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a patient preferably a human
  • diseases in which the ⁇ -secretase enzyme is involved such as Alzheimer's disease
  • the invention is also directed to methods of inhibiting BACEl enzyme activity, by administering a therapeutically effective amount of a spiropiperidine compound of any of the embodiments of formula (J), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, to a mammal or patient in need thereof.
  • the invention is directed to methods of inhibiting BACE2 enzyme activity, by administering a therapeutically effective amount of a spiropiperidine compound of any of the embodiments of formula (I), (II), (HI), or (TV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, to a mammal or patient in need thereof.
  • the invention is also directed to methods of treating a patient (preferably a human) for diseases in which the ⁇ -secretase enzyme is involved, such as Alzheimer's disease, by administering a therapeutically effective amount of a spiropiperidine compound of any of the embodiments of formula (I), (JI), (III), or (IV), or a pharmaceutically acceptable salt thereof, in combination with a P450 inhibitor, such as ritonavir, and a pharmaceutically acceptable carrier.
  • a spiropiperidine compound of any of the embodiments of formula (I), (JI), (III), or (IV), or a pharmaceutically acceptable salt thereof in combination with a P450 inhibitor, such as ritonavir, and a pharmaceutically acceptable carrier.
  • the invention is also directed to pharmaceutical compositions for the treatment of diseases in a patient (preferably a human) in which the ⁇ -secretase enzyme is involved, such as Alzheimer's Disease, which include a therapeutically effective amount of a compound of any of the embodiments of formula (I) 5 (II), (ITl), or (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention is also directed to pharmaceutical compositions for the treatment of diseases in mammals (preferably humans) in which the ⁇ -secretase enzyme is involved, such as Alzheimer's Disease, which include a therapeutically effective amount of a compound of any of the embodiments of formula (I), (II), (JTL), or (TV), or a pharmaceutically acceptable salt thereof, together with a P450 inhibitor, such as ritonavir, and a pharmaceutically acceptable carrier.
  • diseases in mammals preferably humans
  • the ⁇ -secretase enzyme such as Alzheimer's Disease
  • a therapeutically effective amount of a compound of any of the embodiments of formula (I), (II), (JTL), or (TV), or a pharmaceutically acceptable salt thereof, together with a P450 inhibitor, such as ritonavir, and a pharmaceutically acceptable carrier such as ritonavir
  • the invention is further directed to a method for the manufacture of a medicament or a composition for inhibiting ⁇ -secretase enzyme activity in mammals (preferably humans) and animals comprising combining a therapeutically effective amount of a compound of any of the embodiments of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.
  • the invention is also directed to a method for the manufacture of a medicament or a composition for treating diseases in which the ⁇ -secretase enzyme is involved, such as Alzheimer's Disease, in mammals (preferably humans), comprising combining a therapeutically effective amount of compound of any of the embodiments of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.
  • the invention is also directed to a method for the manufacture of a medicament or a composition for treating diseases in which the ⁇ -secretase enzyme is involved, such as Alzheimer's Disease, in mammals (preferably humans), comprising combining a compound of any of the embodiments of formula (I), (II), (III), or (TV), or a pharmaceutically acceptable salt thereof, and a P450 inhibitor, such as ritonavir, with a pharmaceutically acceptable carrier.
  • alkyl by itself or as part of another substituent, means a saturated straight or branched chain hydrocarbon radical having the number of carbon atoms designated (e.g., Ci_io alkyl means an alkyl group having from one to ten carbon atoms).
  • Preferred alkyl groups for use in the invention are C ⁇ - ⁇ alkyl groups, having from one to six carbon atoms.
  • Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.
  • Co alkyl for example in the term “-Coalkyl-C6-12 aryl”, refers to a bond.
  • alkylene by itself or as part of another substituent, means a saturated straight or branched chain divalent hydrocarbon radical having the number of carbon atoms designated.
  • alkenyl by itself or as part of another substituent, means a saturated straight chain divalent hydrocarbon radical having the number of carbon atoms designated.
  • alkenyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical having a single carbon-carbon double bond and the number of carbon atoms designated (e.g., C2-10 alkenyl means an alkenyl group having from two to ten carbon atoms).
  • Preferred alkenyl groups for use in the invention are C2-6 alkenyl groups, having from two to six carbon atoms.
  • Exemplary alkenyl groups include ethenyl and propenyl.
  • alkynyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical having a single carbon-carbon triple bond and the number of carbon atoms designated (e.g., C2-10 alkynyl means an alkynyl group having from two to ten carbon atoms).
  • Preferred alkynyl groups for use in the invention are C2-6 alkynyl groups, having from two to six carbon atoms.
  • Exemplary alkynyl groups include ethynyl and propynyl.
  • cycloalkyl by itself or as part of another substituent, means a saturated cyclic hydrocarbon radical having the number of carbon atoms designated (e.g., C3.42 cycloalkyl means a cycloalkyl group having from three to twelve carbon atoms).
  • C3.42 cycloalkyl means a cycloalkyl group having from three to twelve carbon atoms.
  • cycloalkyl as used herein includes mono-, bi- and tricyclic saturated carbocycles, as well as bridged and fused ring carbocycles, such as spiro fused ring systems.
  • Preferred cycloalkyl groups for use in the invention are monocyclic C3-8 cycloalkyl groups, having from three to eight carbon atoms.
  • Exemplary monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Exemplary bridged cycloalkyl groups include adamantly and norbornyl.
  • Exemplary fused cycloalkyl groups include decahydronaphthalene.
  • heterocyclic by itself or as part of another substituent. means a cycloalkyl group as defined above, in which one or more of the ring carbon atoms is replaced with a heteroatom (such as N or O).
  • Suitable non-aromatic heterocyclic groups for use in the invention include piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl and imidazolildinyl.
  • Preferred heterocyclic groups for use in the invention have four to eight ring atoms and a single nitrogen or oxygen heteroatom.
  • the substituent When a heterocyclic group as defined herein is substituted, the substituent may be bonded to a ring carbon atom of the heterocyclic group, or to a ring heteroatom (Le., a nitrogen, oxygen or sulfur), which has a valence which permits substitution. Preferably, the substituent is bonded to a ring carbon atom.
  • the point of attachment may be at a ring carbon atom of the heterocyclic group, or on a ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which has a valence which permits attachment.
  • the attachment is at a ring carbon atom.
  • aryl by itself or as part of another substituent, means an aromatic or cyclic radical having the number of carbon atoms designated (e.g., C ⁇ - 10 81 Yl means an aryl group having from six to ten carbons atoms).
  • aryl includes multiple ring systems (such as fused ring systems) as well as single ring systems, and includes multiple ring systems wherein part of the molecule is aromatic and part is non-aromatic.
  • the preferred single ring aryl group for use in the invention is phenyl.
  • Preferred fused ring aryl groups include naphthyl, tetrahydronaphthyl and indanyl.
  • halo or halogen includes fluoro, chloro, bromo and iodo.
  • heteroaryl by itself or as part of another substituent, means an aromatic cyclic group having at least one ring heteroatom (O, N or S).
  • heteroaryl includes multiple ring systems as well as single ring systems.
  • Preferred heteroaryl groups have from 5 to 12 ring atoms.
  • heteroaryl groups include pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, indazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl and benzoxazolyl.
  • Preferred heteroaryl groups for use in the invention have 5 or 6 ring atoms.
  • Exemplary groups include furanyl, thienyl and pyridyl.
  • the substituent When a heteroaryl group as defined herein is substituted, the substituent may be bonded to a ring carbon atom of the heteroaryl group, or on a ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which has a valence which permits substitution. Preferably, the substituent is bonded to a ring carbon atom.
  • the point of attachment may be at a ring carbon atom of the heteroaryl group, or on a ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which has a valence which permits attachment.
  • the attachment is at a ring carbon atom.
  • BACE beta-secretase
  • BACEl BACEl
  • BACE2 ⁇ -secretase
  • BACEl is a 501 amino acid membrane-bound aspartic protease.
  • BACEl has all the known functional properties and characteristics of ⁇ -secretase.
  • BACE2 also called Asp-1 or memapsin-1, is a second member of the BACE family of membrane-bound aspartic proteases. See Roggo, Current Topics in Medicinal Chemistry, 2002, 2:359-370, for a further discussion of the differences between BACEl and BACE2.
  • the compounds of the invention are inhibitors of both the BACEl and BACE2 enzyme.
  • the compounds of the invention have at least two asymmetric centers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule.
  • the 5-carbon and 7-carbon of the spiropiperidine ring are chiral.
  • the compounds of formula (I) and (IA) may be present as two racemic diastereomers, or in four stereochemically pure forms.
  • diastereomeric forms for compounds of formula (I) are depicted below, as diastereomers (I'), where the amine of the spiro center and the R4 group are cis to one another, and (I"), where the amine of the spiro center and the R.4 group are trans to one another.
  • the diastereomer (F) is the 5(S 5 R), 7(S 5 R) configuration
  • the diastereomer (I") is the 5(R,S),7(S,R) configuration.
  • Each of (F) and (1") may be present as a racemic mixture, or in one of two enantiomeric forms, as shown below with compound (F'), as compounds (I") and (F'*):
  • the diastereomer (II s ) is the 5(S,R), 7(S 3 R) configuration
  • the diastereomer (II") is the 5(R,S),7(S,R) configuration.
  • Compounds described herein may contain one or more double bonds, and may thus give rise to cisltrans isomers as well as other configurational isomers.
  • the present invention includes all such possible isomers as well as mixtures of such isomers.
  • Formulas (I)-(IV) are shown above without a definite stereochemistry at certain positions.
  • the present invention includes all stereoisomers of formulas (I)-(IV) 5 and pharmaceutically acceptable salts thereof.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers or diastereomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art.
  • any enantiomer or diastereomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • the compounds claimed in this invention can be prepared according to the following general procedure methods.
  • Generic Scheme 1 depicts the formation of compounds of the invention. Combination of an isonitrile, an amine salt, a 4-piperidinone in which the nitrogen is bonded to a removable group P, and a cyanate salt are combined in an Ugi reaction similar to that described in I. Ugi, et.al. Angew. Chem. Int. Ed. Engl. I 3 8-21, 1962 to give the intermediate iminohydantoin 1-1.
  • the protecting group P may then be removed by a suitable method (HCl gas in EtOAc, for example, if the protecting group is BOC) to give the amine salt, which may then be derivatized with a suitable aldehyde through a reductive animation procedure similar to that described in J. March, Advanced Organic Chemistry, 3 rd Ed. John Wiley and Sons, NY page 799. Hydrolysis of the iminohydantoin to the hydantoin then may take place under acidic conditions to give the product 1-4.
  • a similar method is outlined in Generic Scheme 2.
  • a suitable boronic ester reagent 2-2 may be prepared and coupled under organometallic catalysis to the iminohydantoin 2-4 to give the biphenyl intermediate 2-5, which is then hydrolyzed to the hydantoin 2-6 as described above.
  • Generic Scheme 3 describes the synthesis of ortho biphenyl examples of type 3-3, 3-4 and 3-5, where R" may be H or Q (piperidine substituent).
  • R may be H or Q (piperidine substituent).
  • Method A starting from 3-1 from International Patent Application WO 2007/011833 involves first a Strecker reaction (similar to that described by J. Cossy in Synthesis 1995 11 1368-1370) with an o-haloaniline to give 3-1 A and its cis isomer which may be separated or taken on together to the next step.
  • a Suzuki coupling and ring closure with chlorosulfonylisocyanate similar to that described by R.Sarges et al.
  • Generic Scheme 4 describes the synthesis of additional examples of the invention. Starting from 3-2 prepared as described above in Generic Scheme 3, the preparation begins with a ring closure with trichloroacetylisocyanate (similar to methods described in International Patent Application WO 2007/011833) to the intermediate iminohydantoin 4-2 which is then reacted with an amine to give the substituted iminohydantoin 4-3. The protecting group is removed with Pd(OH) 2 and H 2 to give 4-4. Further elaboration via alkylation or reductive amination gives examples of type 4-5. Optional Suzuki coupling to further elaborate QR 3 can occur using Pd(O) followed by hydrolysis of the iminohydantoin to then give the hydantoin product 4-6. GENERIC SCHEME 5
  • Generic Scheme 5 A more direct route similar to Generic Scheme 4 that may be used is described in Generic Scheme 5.
  • the mixture of Strecker products obtained in Scheme 4 may be cyclized in the presence of acid to give the hydantoin product 5-3 directly.
  • the piperidine nitrogen protecting group may then be removed with a suitable method like hydrogenation and the nitrogen then derivatized by a suitable method, such as reductive amination or alkylation, using the methods described above, to give the products 5-5.
  • Generic Scheme 6 depicts a variation on generic scheme 3 in which the hydantoin ring formation takes place first and then is followed with the palladium catalyzed coupling of an alkyne to yield compounds of the type 6-1.
  • GENERIC SCHEME 7
  • Generic Scheme 7 outlines the preparation of cyclic ureas and carbamates covered by the scope of the invention.
  • the product of the Strecker reaction prepared in a manner similar to that described in J. Cossy, et.al. Synlett 1998, 251-252 described in Generic Scheme 3 above is reduced with a suitable reducing agent like DIBAL ,or NaBH 45 Or with a suitable catalyst like Raney Nickel or Rhodium and hydrogen to give the alcohol and amine products, which are cyclized with carbonyldiimidazole to give the cyclic urea or carbamate 7-4.
  • a suitable reducing agent like DIBAL ,or NaBH 45
  • a suitable catalyst like Raney Nickel or Rhodium and hydrogen
  • the urea products may then be further functionalized by alkylation with alkyl halides and a suitable base like NaH to give products 7-5, or if QR3 is a removable group like benzyl, it may be removed via reduction with a suitable catalyst and H2 to give products 7-6 which may be alkylated to give products 7-7 and 7-8.
  • Generic Scheme 8 outlines the preparation of compounds having a variety of substituents on the nitrogen of the hydantoin moiety.
  • the iminohydantoin 8-1 the synthesis of which is described in International patent application WO2007/011833, is treated with aqueous acid and heat to afford the hydantoin 8-2.
  • This material then may be treated with a base like potassium carbonate and an alkylating agent like an alkyl halide in a suitable solvent like DMF to give the alkylated product 8-3.
  • Generic Scheme 9 outlines another method of preparing compounds having a variety of substituents on the nitrogen of the hydantoin moiety.
  • the hydantoin 8-2 (described in Generic Scheme 8) is treated with a suitable alcohol under Mitsunobu reaction conditions, employing reagents like DEAD and triphenylphosphine to give the products 9-1.
  • Generic Scheme 10 outlines another method of preparing compounds having a variety of substituents on the nitrogen of the hydantoin moiety.
  • the hydantoin 8-2 (described in Generic Scheme 8) is treated with a suitable boronic acid under in the presence of a copper catalyst like copper acetate to give the N-aryl analogs 10-1.
  • Generic Scheme 11 outlines another method of preparing compounds having different combinations of substituents on the nitrogen of the hydantoin and on the piperidine nitrogen, hi this method, the hydantoin 8-2 (described in Generic Scheme 8) is treated with a suitable base like potassium carbonate and an alkylating agent to give the N-alkylated intermediate 11-1.
  • the benzyl group on the piperidine nitrogen is then removed with hydrogenation in the presence of a palladium catalyst like palladium hydroxide to give intermediate 11-2.
  • the piperidine nitrogen is then treated with a suitable aldehyde under reductive amination conditions with a reagent like triacetoxyborohydride to give the product 11- 3.
  • Generic Scheme 12 outlines another method of preparing compounds having different combinations of substituents on the nitrogen of the hydantoin and on the piperidine nitrogen, and allows for the piperidine substituent to be incorporated last.
  • the benzyl group on the hydantoin 8-2 (described in Generic Scheme 8) piperidine nitrogen is removed with hydrogenation in the presence of a palladium catalyst like palladium hydroxide to give intermediate 12-1.
  • the piperidine nitrogen is then alkylated with a suitable alkylating agent to give intermediate 12-2, which is then treated with a suitable base like potassium carbonate and an alkylating agent to give the N-alkylated intermediate 12-3.
  • Generic Scheme 13 outlines another method of preparing compounds covered in the scope of the invention, in particular those that possess a cyano substituent on the phenyl group.
  • Acid hydrolysis of the iminohydantoin 13-1 (prepared in a manner similar to that described for example 11-6 in WO2007/011833 by using 3-cyanoaniline and condition A) using an aqueous acid like HCl is followed by hydrogenation with a catalyst like palladium hydroxide to give the intermediate 13-3.
  • Alkylation of the piperidine nitrogen using a base like DIEA, then alkylation of the hydantoin nitrogen using a base like K 2 CO 3 gives the products 13-5.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • the compounds of the invention may be mono, di or tris salts, depending on the number of acid functionalities present in the free base form of the compound.
  • Free bases and salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • Such acids include acetic, trifluoroacetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, trifluoroacetic, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
  • the present invention is directed to the use of the compounds of formulas (I) to (IV) disclosed herein as.inhibitors of ⁇ -secretase enzyme activity or ⁇ -site amyloid precursor protein- cleaving enzyme ("BACE") activity, in a patient or subject such as a mammal in need of such inhibition, comprising the administration of an effective amount of the compound.
  • BACE ⁇ -secretase enzyme activity or ⁇ -site amyloid precursor protein- cleaving enzyme
  • ⁇ -secretase enzyme ⁇ -site amyloid precursor protein-cleaving enzyme
  • BACE ⁇ -site amyloid precursor protein-cleaving enzyme
  • the compounds of the present invention have utility in treating, ameliorating, controlling or reducing the risk of Alzheimer's disease.
  • the compounds may be useful for the prevention of dementia of the Alzheimer's type, as well as for the treatment of early stage, intermediate stage or late stage dementia of the Alzheimer's type.
  • the compounds may also be useful in treating, ameliorating, controlling or reducing the risk of diseases mediated by abnormal cleavage of amyloid precursor protein (also referred to as APP) 5 and other conditions that may be treated or prevented by inhibition of ⁇ -secretase.
  • APP amyloid precursor protein
  • Such conditions include mild cognitive impairment, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld- Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses. diabetes and atherosclerosis.
  • the subject or patient to whom the compounds of the present invention is administered is generally a human being, male or female, in whom inhibition of ⁇ -secretase enzyme activity is desired, but may also encompass other mammals, such as dogs, cats, mice, rats, cattle, horses, sheep, rabbits, monkeys, chimpanzees or other apes or primates, for which inhibition of ⁇ - secretase enzyme activity or treatment of the above noted disorders is desired.
  • combinations of the compounds of the present invention with other drugs in either unit dose or kit form include combinations with anti-Alzheimer's agents, for example other beta-secretase inhibitors or gamma-secretase inhibitors; glycine transport inhibitors, tau phosphorylation inhibitors; blockers of A ⁇ oligomer formation; p25/CDK5 inhibitors; HMG- CoA reductase inhibitors; PPAR gamma agonists, such as pioglitazone and rosiglitazone; NK1/NK3 receptor antagonists; NSAID's including ibuprofen; vitamin E; anti-amyloid antibodies, including anti-amyloid humanized monoclonal antibodies; COX-2 inhibitors; anti- inflammatory compounds, such as (R)-flurbiprofen; CB-I receptor antagonists or CB-I receptor inverse agonists; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NM
  • composition as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • This term in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation, hi the pharmaceutical composition the active compound, which is a compound of the invention (of formulas (I), (F), (II), (U'), (IH) and (III')), is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the invention and a pharmaceutically acceptable carrier.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • the pharmaceutical compositions of the invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in- water emulsion or as a water-in-oil liquid emulsion.
  • the compounds of the invention may also be administered by controlled release means and/or delivery devices.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets may contain a compound of the invention in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alg ⁇ nic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a tablet containing a composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, a compound of the invention in a free- flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about O.lmg to about 500 mg of the active ingredient and each cachet or capsule preferably containing from about O.lmg to about 500 mg of the compound of the invention.
  • compositions for oral use may also be presented as hard gelatin Capsules wherein the compound of the invention is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the compound of the invention is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • compositions include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions, hi addition, oily suspensions may be formulated by suspending the compound of the invention in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension, or in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound of the invention, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can also be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories.
  • suitable carriers include cocoa butter and other materials commonly used in the art.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • administering a should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individual's body in a therapeutically useful form and therapeutically useful amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, IM, or IP, and the like; transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.
  • oral dosage forms such as tablets, capsules, syrups, suspensions, and the like
  • injectable dosage forms such as IV, IM, or IP, and the like
  • transdermal dosage forms including creams, jellies, powders, or patches
  • buccal dosage forms inhalation powders, sprays, suspensions, and the like
  • rectal suppositories rectal suppositories.
  • an effective amount or “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • treatment means any administration of a compound of the invention and includes (1) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (2) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
  • controlling includes preventing treating, eradicating, ameliorating or otherwise reducing the severity of the condition being controlled.
  • compositions containing compounds of the invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • unit dosage form is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person administering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages.
  • Typical examples of unit dosage forms are tablets or capsules for oral administration, single dose vials for injection, or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.
  • compositions containing compounds of the invention may conveniently be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person adminstering the drug to the patient.
  • kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug. to the patient.
  • the compounds of the invention are administered at a daily dosage of from about 0.1 mg to about 100 mg per kg of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 mg to about 2000 mg, preferably from about 0.1 mg to about 20 mg per kg of body weight. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the amount of the compound of the invention that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration to humans may conveniently contain from about 0.005 mg to about 2.5 g of a compound of the invention, compounded with an appropriate and convenient amount of carrier material.
  • Unit dosage forms will generally contain between from about 0.005 mg to about 1000 mg of the compound of the invention, typically 0.005 mg, 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg, administered once, twice or three times a day.
  • ECL Assay A homogeneous end point electrochemiluminescence (ECL) assay is performed using a biotinylated BACE substrate.
  • the Km of the substrate is greater than 100 ⁇ M and can not be determined due to the limit of solubility of the substrate.
  • a typical reaction contains approximately 0.1 nM enzyme, 0.25 ⁇ M of the substrate, and buffer (50 mM NaOAc, pH 4.5, 0.1 mg/ml BSA, 0.2% CHAPS, 15 mM EDTA and 1 mM deferoxamine) in a total reaction volume of 100 ⁇ l. The reaction proceeds for 30 min and is then stopped by the addition of 25 ⁇ L of 1 M Tris-HCl, pH 8.0.
  • the resulting enzymatic product is assayed by adding a ruthenylated antibody which specifically recognizes the C-terminal residue of the product. Streptavidin coated magnetic beads are added into the solution and the samples are subjected to M-384 (Igen Inc., Gaithersburg. MD) analysis. Under these conditions, less than 10% of substrate is processed by BACE 1.
  • the enzyme used in these studies is soluble (transmembrane domain and cytoplasmic extension excluded) human protein produced in a baculovirus expression system.
  • 12 concentrations of inhibitors are prepared starting from 100 ⁇ M with three fold series dilution. Solutions of the inhibitor in DMSO are included in the reaction mixture (final DMSO concentration is 10 %). All experiments are conducted at rt using the standard reaction conditions described above. To determine the IC50 of the compound, a four parameter equation is used for curve fitting. The errors in reproducing the dissociation constants are typically less than two-fold.
  • the compounds of the following examples had activity in inhibiting the beta- secretase enzyme in the aforementioned assay, generally with an IC50 from about 1 nM to 200 ⁇ M. Such a result is indicative of the intrinsic activity of the compounds in use as inhibitors of beta-secretase enzyme activity.
  • Step 2 IB (0.253g, 0.910mol), KOAc (0.268g, 3.0eq), ID (0.208g, 0.9eq) and PdCl 2 (dppf) (0.074g, 0.1 eq) were added in a round bottom flask. Dry DMF (5ml) was then added under N 2 protection. The resultant mixture was stirred for a while and put into an 80 0 C oil bath. The reaction was followed by LCMS. Upon completion (2-4 h), reaction mixture was extracted with EtOAc / water three or four times, washed with brine twice. The resultant EtOAc solution was dried with MgSO 4 and concentrated to afford crude Intermediate I. EI-MS m/z: 326 (M + H) +
  • Step 2 HB (3.21g, 0.0122mol), KOAc (3.58g, 3.0eq), HD (4.01g, 1.3eq) and PdCl 2 (dppf) (0.993g, O.leq) were added in a round bottom flask. Dry DMF (60 ml) was then added under N 2 protection. The resultant mixture was stirred for a while and put into an 80 0 C oil bath. The reaction was followed by LCMS. Upon completion (2-4hrs), reaction mixture was extracted with EtOAc / water three or four times, washed with brine twice. The resultant EtOAc solution was dried with MgSO 4 and concentrated to afford crude IIC. EI-MS m/r. 312 (M + H) + .
  • Step 1 To a stirred solution of 4-bromobenzenesulfonyl chloride (2.5 g, 10.0 mmol) in 50.0 mL
  • Step 2 A mixture of IIIA (2.4 g 5 9.0 mmol), bis(pinacolato)diboron (2.5 g, 10.0 mmol) and potassium phosphate (42.5 g, 20.0 mmol) in 50 mL DMF 5 was purged with nitrogen gas, then added PdCl 2 (dppf) (4.0 g, 5.6 mmol). The solution was heated at 80 0 C for 3h, cooled to it and quenched with water. The product was extracted three times with ethyl acetate, washed with water, saturated sodium bicarbonate and brine.
  • Step 1 To a stirred solution of 4-bromo-2-methylbenzoic acid (0.43 g, 2.0 mmol) in 10.0 mL THF, was added carbonyl diimidazole (0.356 g, 2.2 mmol). The resulting mixture was stirred at rt for 5 min, then added dimethylamine hydrochloride salt (0.179 g, 2.2 mmol), followed by triethylamine (0.56 mL, 4.0 mmol). The solution was stirred at rt for 3h, then quenched with water. The product was extracted three times with ethyl acetate, washed with water, saturated sodium bicarbonate, IN HCl and brine. The solution was dried over magnesium sulfate, filtered, and concentrated to yield IVA as a white solid which was used for next step without purification. EI-MS m/z: 244.0.5 (M + H) + .
  • Step 2 A mixture of IVA (0.376 g, 1.55 mmol), bis-(pinacolato)diboron (0.472 g, 1.86 mmol) and potassium acetate (0.761 g, 7.75 mmol) in 6.0 mL DMF, was purged with nitrogen gas, then added PdCl 2 (dppf) (340.0 mg, 0.465 mmol). The solution was heated at 80 0 C for 3h, cooled to rt, then quenched with water.
  • PdCl 2 dppf
  • Step 1 To a stirred solution of 5-bromo-thiophene-2-sulfonyl chloride (1.05 g, 4.0 mmol) in 20.0 mL THF at O 0 C, was added 4.0 mL of 2M dimethylamine in THF. The solution was stirred at rt for 3 h, then quenched with water. The product was extracted three times with ethyl acetate, washed with water, IN HCl and brine. The solution was dried over magnesium sulfate, filtered, and concentrated to yield VA as a solid which was used for next reaction step without purification.
  • Step 2 A mixture of 2-bromo-5-fiuoro-phenylamine (380.0mg, 2.0mmol), bis(pinacolato)- diboron (559.0 mg, 2.2 mmol) and potassium acetate (981.0 mg, 10.0 mmol) in 10.0 mL DMF, was purged with nitrogen gas, then added PdCl 2 (dppf) (292.4.0 mg, 0.4 mmol). The solution was heated at 80 0 C for 3h, cooled to rt.
  • Step 1 l-[(2'-methylbiphenyl-3-yl)methyl]piperidin-4-one (Intemediate VI) To a suspension of 1 ; 4-dioxa-8-azaspiro[4.5]decane (3.5 ml, 27.0 mmol) in 1 ,2-dichloroethane (200 ml) were added 2'-methylbiphenyl-3-carbaldehyde (5.0 g, 25.5 mmol) and acetic acid (1 ml). The reaction mixture was allowed to stir for 1 h at rt. Sodium triacetoxyborohydride (10.8 g, 51.0 mmol) was added to the reaction, and the mixture continued to stir for 18 h at rt.
  • the reaction was quenched by the addition of a saturated sodium bicarbonate solution, diluted with dichloromethane, and allowed to stir vigorously for 1 h. The organic portion was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude oil was purified via flash chromatography (silica gel, 5% methanol/DCM) to yield 8-[2'- methylbiphenyl-3-yl)methyl]-l,4-dioxa-8-azaspiro[4.5]decane (54%). The material was dissolved in concentrated HCl (5.0 ml), stirred at rt for 12 h, and then at reflux for 2 days.
  • concentrated HCl 5.0 ml
  • the reaction was concentrated under vacuum and quenched with saturated sodium bicarbonate solution.
  • the product was extracted with dichloromethane, and the organic portion was dried over sodium sulfate, filtered, and concentrated under vacuum.
  • the material was purified via flash chromatography (silica gel, 0-5% methanol/dichloromethane) to yield l-[(2'- methylbiphenyl-3-yl)methyl]piperidin-4-one.
  • Step 2 tert-Butyl l-(3-fluorophenyl)-4-(methylamino)-2-oxo-l,3,8-triazaspiro[4.5]dec-3-ene-8- carboxylate 1-2
  • Step 3 1 -(3-fluorophenyl)-4-methylammonio)-2-oxo- 1 ,3 -diaza-8-azoniaspiro[4.5]dec-3-ene Dihydrochloride 1-3
  • Step 4 l-(3-fluorophenyl)-8-[(2 I -methyl-l,r-biphenyl-3-yl)methyl]-2 s 4-dioxo-1.3-diaza-8- azoniaspiro[4.5]decane trifluoroacetate (Example 1)
  • Step 1 Compound 2A (0.095Og, 0.166mmol, compound 15-1 in International Patent Publication WO2006/044497) and Intermediate I (0.131 g, 2.0eq), the palladium catalyst (AcO) 2 Pd(Cy 2 NH) 2 (0.020Og, 0.65eq) and K 3 PO 4 (0.034Og, 3.0eq) were weighed into a 1 dram vial. A magnetic stir bar was added, followed by absolute ethanol (ImL). The vial was capped, and placed to stir in a 80 deg C aluminum block over a hot plate. When the reaction showed black palladium precipitate (several hours), the reaction was cooled to room temperature. The reaction was then filtered through celite, and the resulting solution was purified by HPLC to afford Compound 2B. EI-MS m/z: 690 (M + H) +
  • Step 3 Intermediate II (2.8Og, 0.00951mol) 3
  • Compound 3A (Example 14-4 of International Patent Publication WO2006/044497) 2.77g, 1.1 eq), HOAc (78ml) were mixed and heated at 6O 0 C until the solid was dissolved. The reaction mixture was cooled down. Trimethylsilyl cyanide (3.80ml, 3.0eq) added dropwise at 0 0 C. The reaction mixture was then allowed to warm up to rt and stirred overnight. The reaction was quenched with ammonium hydroxide in ice until the pH reached 10, then filtered. The solid was washed with water and Et 2 ⁇ and dried under vacuum at 4O 0 C to afford compound 3B. EI-MS m/z: 295 (M + H) + .
  • Step 4 To the solution of Compound 3B (0.25Og, 0.454mmol) in DCM (3ml), was added ' dropwise at O 0 C chlorosulfonyl isocyanate (0.043ml, 1.1 eq). The mixture was stirred at rt for 35 min. Water (ImI) was then added. The reaction mixture was stirred for 1 h. IM aqueous HCl (9ml)and THF (l-2ml) were added and the resulting mixture was stirred and heated at 60 0 C for 2 days. The mixture was extracted with EtOAc / saturated NaHCOa aqueous solution twice, washed with brine twice, dried with MgSO 4 , concentrated and purified by HPLC to afford Example 3. ⁇ EI-MS m/z: 595 (M + H) +
  • Step 5 To a stirred solution of Example 3 (0.02Og, 0.0336mmol) in DMF (1.5ml), was added NaH (60% dispersion in mineral oil) (0.013g, 10eq) at 0 0 C. MeI (0.0020ml, l.Oeq) was then added. The reaction was allowed to warm up to rt and stirred for another 30 min, then quenched with saturated aqueous NH 4 Cl solution, extracted with Et2 ⁇ twice, washed with brine twice, dried with MgSO 4 , concentrated and purified by preparative TLC (0.8% 2M ammonia in MeOH/DCM) to afford Example 4. EI-MS m/z: 609 (M + H) +
  • Step 6 To a stirred solution of Example 3 (0.020g, 0.0336mmol) in DMF (1.5ml), was added NaH (60% dispersion in mineral oil) (0.013g, 10eq) at O 0 C. "PrI (0.0048ml, l.Oeq) was then added. The reaction mixture was warmed to rt and stirred for another 30 min. The reaction was quenched with saturated aqueous NH 4 Cl solution, extracted with Et 2 O twice, washed with brine twice, dried with MgSO 4 , concentrated and purified by preparative TLC (0.5% 2M ammonia in MeOH/DCM) to give Example 5. EI-MS m/z: 637 (M + H) + .
  • Step 3 To a solution of the amine 7 A (Example 15-46 in International Patent Publication WO2006/044497) (84.7 mg, 0.2mmol) in 2.OmL DMF 5 was added potassium carbonate (30.4 mg, 0.22 mmol), followed by benzyl bromide (27.0 ⁇ L, 0.22mmol). The solution was heated at 80 0 C for 15h, cooled to rt then quenched with water. The product was extracted three times with ethyl acetate, washed with water and brine. The solution was dried over magnesium sulfate, filtered, concentrated and purified by silica gel column chromatography (100% EtOAc) to provide 7B. EI-MS m/z: 513.15 (M + H) + .
  • Step 4 A mixture of 7B (50.2 mg, 0.1 mmol), Intermediate HI (62.2 mg, 0.2 mmol), potassium phosphate (43.6 mg, 0.2 mmol), and in 2.0 mL ethanol, was purged with nitrogen gas, then added DAPCy (58.6 mg, 0.1 mmol). The solution was heated at 80 0 C for overnight, or until complete disappearance of compound 7B(monitored by LCMS). The crude was purified by preparative HPLC to provide 7C as an amine-TFA salt. EI-MS m/z: 618.30 (M + H) + .
  • Step 5 A suspension of compound 7C (10.0 mg, 0.014 mmol) in 1.0 mL of IM HCl was heated at 80 0 C overnight. The final product was purified by preparative HPLC to provide Example 7 as an amine-TFA salt.
  • Step 1 A mixture of 8 A (compound 2 A from Example 2) (60.0 mg, 0.1 mmol), Intemediate IV (31.9 mg, 0.11 mmol), potassium phosphate (42.5 mg, 0.2 mmol), and in 2.0 mL ethanol, was purged with nitrogen gas, then added DAPCy (29.0 mg, 0.05 mmol). The solution was heated at 80 0 C until complete disappearance of compound 8A (monitored by LCMS). The crude reaction mixture was purified by preparative HPLC to provide 8B as the amine-TFA salt. EI-MS m/z: 654.30 (M + H) + .
  • Step 4 A suspension of compound 8B (10.0 mg, 0.013 mmol) in 1.0 mL of IM HCl was heated at 80 0 C overnight. The final product was purified by preparative HPLC to provide Example 8 as an amine-TFA salt.
  • Step 1 To an ice-cold solution of l-(3-isopropoxybenzyl)-piperidin-4-one (Example 14-4 of International Patent Publication WO2006/044497) 79.5 mg, 0.3 mraol) and lntemediate V (99.4 mg, 0.33 mmol) in glacial acetic acid (1.5 mL), was added slowly trimethylsilyl cyanide (44.0 ⁇ L, 0.33 mmol). The reaction mixture was kept at O 0 C for 5 min then rt for 30 min. The resulting mixture was quenched with ammonium hydroxide in ice until the pH reached 10 then extracted two times with dichloromethane.
  • Step 4 To an ice cold solution of 9A (108.4 mg, 0.19 mmol) in 1.0 mL chloroform, was added dropwise chlorosulfonyl isocyanate (49.7 ⁇ L, 0.22 mmol) and stirred at rt for 30 min, then added 0.50 mL of water. The reaction mixture was stirred for another Ih at rt then added to an ice cold aqueous solution of H2S (156.1 mgNa 2 S + 4.0 mL H 2 O + 1.0 mL acetic acid), which was prepared right before use. The resulting reaction was stirred at rt for 24 h then hydrolyzed with 1.0 mL IN HCl at 80 0 C over a 5h period.
  • the reaction mixture was made basic with saturated sodium bicarbonate solution, and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated. The final product was purified by preparative HPLC to provide Example 9 as an amine-TFA salt.
  • Example 16 was made from palladium catalyzed coupling of N- methyl-iV-prop-2-yn-l-ylmethanesulfonarnide (J. Med. Chem. 1988, 31 577-582) and example 14 using Pd(tBu3P)2 , CuI, DIEA in dioxane.
  • EXAMPLE 16 A ALTERNATIVE PREPARATION OF EXAMPLE 16
  • Step 1 (5R 5 7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3,8- triazaspiro[4.5]decane-2 5 4-dione (Example 16 * )
  • Step 1 17B: (5R,7S)-(5S,7R)-l-benzyl-4-(4'-bromo-4-fluoro-l,l t -biphenyl-2-yl)-2- methylpiperidine-4-carbonitrile
  • the reaction was poured onto cold ammonium hydroxide and crushed ice and adjusted to pH 10.
  • the product was extracted with dichloromethane (3x50 ml), washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum.
  • the crude oil was purified via flash chromatography (silica, 0-20% EtOAc/hexanes) to isolate both (5R, 7R)-(5S7S) and (5R,7S)-(5S,7R)-l-benzyl-4-(4 l -bromo-4-fluoro-l,l'-biphenyl-2-yl)-2- methylpiperidine-4-carbonitrile.
  • Step 2 17C: (5R,7S)-(5S,7R)-l-benzyl-4-[4-fluoro-4'-(methylsulfonyl)-l,l I -biphenyl-2-yl]-2- methylpiperidine-4-carbonitrile
  • reaction mixture was vortexed briefly to dissolve the catalyst and was stirred at 40 0 C for 18 h.
  • the reaction was purified via reverse phase chromatography to yield (5R,7S)-(5S,7R)-1- benzyl-4-[4-fluoro-4'-(methylsulfonyl)- 1 , 1 l -biphenyl-2-yl]-2-methylpiperidine-4-carbonitrile.
  • Step 3 Example 17: (SRJSXSS ⁇ RVS-benzyl-l- ⁇ -fluoro- ⁇ - ⁇ ethylsulfonyO-l ⁇ '-biphenyl ⁇ - yl]-7-methyl-l,3,8-triazaspiro[4.5]decane-2,4-dione
  • reaction mixture was cooled to rt and adjusted to pH 5.5 by the addition of 5N NaOH.
  • crude material was purified via reverse phase chromatography to yield (5R 5 7S),(5S,7R)-8-benzyl-l-[4-fluoro-4'-(methylsulfonyl)-l,r-biphenyl-2-yl]-7-methyl- 1 ,3 ,8-triazaspiro [4.5] decane-2 ,4-dione.
  • Step 2 (5i-,7S)-l-(3-fluorophenyl)-7-methyl-4-(methylammo)-l,3 5 8-triazaspiro[4.5]dec-3-en-2- one (18C).
  • Step 3 (5R,7S)-l-(3-fluorophenyl)-8-(3-iodobenzyl)-7-methyl-4-(methylamino)-l 5 3 5 8- triazaspiro[4.5]dec-3-en-2-one (18D). .
  • a Biotage microwave vial was charged with intermediate (5R,7S)-l-(3-fluorophenyl)-8-(3- iodobenzyl)-7-methyl-4-(methylamino)-l,3 > 8-triazaspiro[4.5]dec-3-en-2-one (60 mg, 0.118 mmol) from step 3 above, PdC ⁇ dppf (4.3 mg, 0.01 mmol) and 2-tolylboronic acid (21 mg, 0.15 mmol).
  • the vial was sealed and put under a nitrogen atmosphere.
  • To the solids was added aqueous 1.5M K. 2 CO 3 (0.24 mL, 0.35 mmol) and degassed THF (0.7 mL).
  • Step 5 (5 J R,75)-l-(3-fluoro ⁇ henyl)-7-methyl-8-[(2'-methylbiphenyl-3-yl)methyl]-l,3,8- triazaspiro[4.5]decane-2,4-dione (Example 18).
  • Step 1 4-[(3-fluorophenyl)amino]-l-[(2'-methylbiphenyl-3-yl)methyl]piperidine-4-carbonitrile (19A)
  • Step 2 4-(aminomethyl)-N-(3 -fluorophenyl)- 1 - [(2 ' -methylbiphenyl-3 -yl)methyl]piperidin-4- amine (19B)
  • Step 3 l-(3-fluorophenyl)-8-[(2'-methylbiphenyl-3-yl)methyl]-l,3,8-triazaspiro[4.5]decan-2- one (19C)
  • Step 4 1 -(3-fluorophenyl)-8-[(2'-methylbiphenyl-3-yl)methyl]-3-(pyridin-2-ylmethyl)-l ,3,8- triazaspiro[4.5]decan-2-one
  • l-(3-fluorophenyl)-8-[(2'-methylbiphenyl-3-yl)methyl]-3-(pyridin-2-ylmethyl)-l,3,8- triazaspiro[4.5]decan-2-one was prepared from l-(3-fluorophenyl)-8-[(2'-methylbiphenyl-3- yl)methyl]-l,3,8-triazaspiro[4.5]decan-2-one (19C 5 30 mg 5 0.07 mmol) and 2- (bromomethyl)pyridine hydrobromide (12 mg, 0.07 mmol) in a manner similar to Example 21.
  • Example 21 To a stirred solution of Example 21 (0.025g, 0.043 lmmol) in DMF (1.5ml), was added NaH (60% dispersion in mineral oil) (0.013g, 10eq) at 0 0 C. MeI (0.0026ml, l.Oeq) was then added. The reaction was allowed to warm to rt and stirred for another 30 min before being quenched with saturated aqueous NH 4 Cl solution. The mixture was extracted with Et 2 O twice and the combined organic extracts were washed with brine twice, dried with MgSO 4 , and purified by preparative HPLC to afford Example 21. EI-MS m/z: 595 (M + H) + at 1.68.
  • Example 24 To a stirred solution of Example 24 (0.025g 5 0.0431mmol) in DMF (1.5ml), was added NaH (60% dispersion in mineral oil) (0.013g, 10eq) at O 0 C. MeI (0.0026ml, l.Oeq) was then added and the reaction was allowed to warm to rt and stirred for another 30 min. The reaction was quenched with saturated aqueous NH 4 Cl solution, extracted with Et 2 O twice, washed with brine twice, dried with MgS ⁇ 4, concentrated and purified by preparative HPLC to afford Example 22. EI-MS m/z: 623 (M + H) + at 1.74.
  • Example 25 the benzyl group of Example 24 was removed with catalyst and hydrogen, and the piperidine alkylated with l-(chloromethyl)-3- isopropoxybenzene (International Patent Application WO 2007/011833 Example 11, Intermediate 11-lOC), l-(chloromethyl)-3- ⁇ [(li?)-l-methylpropyl]oxy ⁇ benzene (above patent, Intermediate 111), or l-(chloromethyl)-3-[(li?)-2-methoxy-l-methylethoxy]benzene, which was made in a manner similar to that described for the above Intermediate III.
  • Step 1 l-benzyl-4-[(3-fluorophenyl)amino]-2-methylpiperidine-4-carbonitrile
  • HOAc 3-fluoroaniline
  • TMSCN 1.97 mL, 14.8 mmol
  • the reaction mixture was poured into 15 mL NH 4 OH and 15g ice.
  • the resulting solution was extracted with CHCI 3 three times, dried with MgSO 4 and concentrated.
  • LRMS (M+l) 324
  • Step 2 1 -benzyl-4-[(3-fluorophenyl)amino] -2-methylpiperidine-4-carbonitrile
  • Step 3 1 -benzyl-4- [(3 -fluorophenyl)amino] -2-methylpiperidin-4-yl ⁇ methanol
  • Step 4 8-benzyl-l-(3-fluorophenyl)-7-methyl-2-oxo-3-oxa-l-aza-8-azoniaspiro[4.5]decane trifluoroacetate
  • Step 1 (5 J R,75)-l-(3-fluorophenyI)-8-(3-isopropoxybenzyI)-3-[2-(4- methoxyphenyl)ethyl]-7-methyl-2,4-dioxo-13-diaza-8-azoniaspiroI4.5]decane trifluoro acetate
  • Example 29 (5 J R,75)-l-(3-fluorophenyI)-8-(3-isopropoxybenzyI)-3-[2-(4- methoxyphenyl)ethyl]-7-methyl-2,4-dioxo-13-diaza-8-azoniaspiroI4.5]decane trifluoro acetate
  • Example 29 The following examples were prepared using a procedure similar to that described for Example 29.
  • the compound was isolated as the TFA salt after chromatography, and in some cases the compound was then isolated as the free base by extraction from a suitable aqueous base like bicarbonate solution with a suitable organic solvent like methylene chloride.
  • the free base could then be transformed to the hydrochloride salt by treatment with an ether solution of HCl.
  • Examples 29-21 and 29-22 were prepared using the esterified form of the alkylating agent, and the ester product was then saponified to the acid.
  • Step 1 (SjRJ ⁇ -l-CS-fluorophenyO-S-CS-furylmethy ⁇ -S-CS-isopropoxybenzyl)- 7-methyl-2,4-dioxo-l,3-diaza-8-azoniaspiro[4.5]decane trifluoroacetate
  • Example 30 The following examples were prepared using a procedure similar to that described for Example 30.
  • the compound was isolated as the TFA salt after chromatography, and in some cases the compound was then isolated as the free base by extraction from a suitable aqueous base like bicarbonate solution with a suitable organic solvent like methylene chloride.
  • the free base could then be transformed to the hydrochloride salt by treatment with an ether solution of HCl.
  • Step 1 (51 ⁇ 7,S)-l-(3-fluorophenyl)-8-(3-isopropoxybeiizyl)-7-methyl-2,4- dioxo-3-phenyl-l,3-diaza-8-azoniaspiro[4.5]decane trifluoroacetate
  • Step 1 (51 ⁇ 7,S)-l-(3-fluorophenyl)-8-(3-isopropoxybeiizyl)-7-methyl-2,4- dioxo-3-phenyl-l,3-diaza-8-azoniaspiro[4.5]decane trifluoroacetate
  • Example 31 The following examples were prepared using a procedure similar to that described for Example 31.
  • the compound was isolated as the TFA salt after chromatography, and in some cases the compound was then isolated as the free base by extraction from a suitable aqueous base like bicarbonate solution with a suitable organic solvent like methylene chloride.
  • the free base could then be transformed to the hydrochloride salt by treatment with an ether solution of HCl.
  • Step 2 (55,7 1 S)-l-(3-fluorophenyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-l ,3,8- triazaspiro[4.5]decane-2,4-dione 32-B
  • A 1.25 M HCl in MeOH (30 ml).
  • Example 32 The following examples were prepared using a procedure similar to that described for Example 32.
  • the compound was isolated as the TFA salt after chromatography, and in some cases the compound was then isolated as the free base by extraction from a suitable aqueous base like bicarbonate solution with a suitable organic solvent like methylene chloride.
  • the free base could then be transformed to the hydrochloride salt by treatment with an ether solution of HCl.
  • Step 1 (5i? 5 7-S)-l-(3-fluorophenyl)-7-methyl-l 5 3 s 8-triazaspiro[4.5]decane-2,4-dione 33-A
  • Example 33 The following examples were prepared using a procedure similar to that described for Example 33.
  • the compound was isolated as the TFA salt after chromatography, and in some cases the compound was then isolated as the free base by extraction from a suitable aqueous base like bicarbonate solution with a suitable organic solvent like methylene chloride.
  • the free base could then be transformed to the hydrochloride salt by treatment with an ether solution of HCl.
  • Step 1 Benzyl (5 ⁇ ,7iS)-l-(3-cyanophenyl)-7-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decane-8- carboxylate Intermediate 34-A
  • Step 2 3-[(5 ⁇ ,7S)-7-methyl-2,4-dioxo-l 5 3,8-triazaspiro[4.5]dec-l-yl]benzonitrile 34-B
  • Step 3 (5i?,75 r )-l-(3-cyanophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-13-diaza-8- azoniaspiro[4.5]decane trifluoroacetate
  • Step 3 (5i?,75 r )-l-(3-cyanophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-13-diaza-8- azoniaspiro[4.5]decane trifluoroacetate
  • Step 4 (5/?,75)-l-(3-cyanophenyl)-8-(3-isopropoxybenzyI)-7-methyl-3-[(5-methyIisoxazol-3- yl)methyI]-2,4-dioxo-13-diaza-8-azoniaspiror4 > 51decane trifluoroacetateExampIe 34-2
  • Example 34 The following examples were prepared using a procedure similar to that described for Example 34. hi some instances, the compound was isolated as the TFA salt after chromatography, and in some cases the compound was then isolated as the free base by extraction from a suitable aqueous base like bicarbonate solution with a suitable organic solvent like methylene chloride. The free base could then be transformed to the hydrochloride salt by treatment with an ether solution of HCl.
  • Step 1 (5/?,7S)-l-(3-fluorophenyl)-8-(3-iodobenzyl)-7-methyl-l,3,8-triazaspiro[4.5]decane-2,4- dione 35-A
  • BSA bovine serum albumin

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Abstract

The present invention is directed to spiropiperidine compounds of formula (I) and tautomers thereof, which are inhibitors of the beta-secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.

Description

TITLE OF THE INVENTION
SPEROPIPERIDINE BETA-SECRETASE INfflBITORS FOR THE TREATMENT OF
ALZHEIMER'S DISEASE
FIELD OF THE INVENTION
The invention is directed to hydantoin, cyclic urea and cyclic carbamate spiropiperidine compounds which are useful as inhibitors of the beta secretase enzyme, and are useful in the treatment of diseases in which the beta secretase enzyme is involved, such as Alzheimer's Disease.
BACKGROUND OF THE INVENTION
Alzheimer's disease is the most common cause of dementia in the elderly and is characterized by a decline in cognitive function. Alzheimer's Disease typically progresses slowly and results in symptoms such as memory loss and disorientation. Existing treatments for Alzheimer's Disease, such as acetylcholinesterase inhibitors, address the symptoms of Alzheimer's Disease but do not target the underlying causes of the disease.
The pathology of Alzheimer's disease is characterized by the deposition of amyloid in the brain in the form of extra-cellular plaques and intra-cellular neurofibrillary tangles. The rate of amyloid accumulation is a combination of the rates of formation, aggregation and egress from the brain. It is generally accepted that the main constituent of amyloid plaques is the 4kD amyloid protein (βA4, also referred to as Aβ, β-protein and βAP) which is a proteolytic product of a precursor protein of much larger size. The amyloid precursor protein (APP or AβPP) has a receptor-like structure with a large ectodomain, a membrane spanning region and a short cytoplasmic tail. The Aβ domain encompasses parts of both extra-cellular and transmembrane domains of APP, thus its release implies the existence of two distinct proteolytic events to generate its NH2- and COOH-termini.
At least two secretory mechanisms exist which release APP from the membrane and generate soluble, COOH-truncated forms of APP (APPS). Proteases that release APP and its fragments from the membrane are termed "secretases." Most APP5 is released by a putative α- secretase which cleaves within the Aβ protein to release α-APPs and precludes the release of intact Aβ. A minor portion of APPS is released by a β-secretase ("β-secretase"), which cleaves near the NH2-terminus of APP and produces COOH-terminal fragments (CTFs) which contain the whole Aβ domain.
Thus, the activity of β-secretase or β-site amyloid precursor protein-cleaving enzyme ("BACE") leads to the cleavage of APP, production of Aβ, and accumulation of β amyloid plaques in the brain, which is characteristic of Alzheimer's disease (see R. N. Rosenberg, Arch. Neurol, vol. 59, Sep 2002, pp. 1367-1368; H. Fukumoto et al, Arch. Neurol., vol. 59, Sep 2002, pp. 1381-1389; J.T. Huse et al, J. Biol. Chem., vol 277, No. 18, issue of May 3, 2002, pp. 16278-16284; K.C. Chen and W.J. Howe, Biochem. Biophys. Res. Comm, vol. 292, pp 702-708, 2002). Therefore, therapeutic agents that can inhibit β-secretase or BACE may be useful for the treatment of Alzheimer's disease.
The compounds of the present invention are useful for treating Alzheimer's disease by inhibiting the activity of β-secretase or BACE, thus preventing the formation of insoluble Aβ and arresting the production of Aβ .
SUMMARY OF THE INVENTION
The present invention is directed to spiropiperidine compounds represented by general formula (I)
and individual enantiomers and diasteroisomers thereof, and pharmaceutically acceptable salts thereof, which are useful as inhibitors of the β-secretase enzyme.
The invention is also directed to pharmaceutical compositions which include a therapeutically effective amount of a compound of formula (I), or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. The invention is also directed to methods of treating mammals for diseases in which the β-secretase enzyme is involved, such as Alzheimer's disease, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention is directed to hydantoin, cyclic carbamate and urea spiropiperidine compounds represented by general formula (I)
wherein
X is selected from the group consisting of (I) N-RA
(2) O, and
(3) S5 and R5 is selected from the group consisting of
(a) hydrogen,
(b) -Cl-IO alkyl, (c) -C2-10 alkenyl, .
(d) -C3-I2 cycloalkyl,
(e) -Cθ-6 alkyl-aryl, and
(f) -Cθ-6 alkyl-heteroaryl wherein said alkyl, alkenyl, cycloalkyl, aryl and heteroaryl R5 moiety is optionally substituted with one or more
0) aryl,
(ii) heteroaryl,
(iii) halogen,
(iv) -Ci-IO alkyl,
(V) -OCi-IO alkyl,
(vi) -C3-I2 cycloalkyl,
(vii) -NC(=O)-R6,
(viii) -C(=O)NR6R6',
(ix) -C(=O)-OR6,
(x) -C(=O)-R6,
(xi) -CN
(xii) -NR6R6'9 wherein said aryl, akly, cycloalkyl and heteroaryl moiety is optionally substituted with one or more
(I) halogen,
QI) -Ci-6 alkyl,
(JE) -OC 1-6 alkyl,
RlA and RlB are each hydrogen, provided that when X is NR5, then RlA and RlB may together form =O;
R2 is selected from the group consisting of (1) hydrogen, (2) -Ci_io alkyl, (3) -C2-IO alkenyl, (4) -C2-10 alkynyl,
(5) -C3-12 cycloalkyl,
(6) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen,
(7) aryl, and
(8) heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic group, alkenyl, alkynyl, aryl or heteroaryl R2 moiety is optionally substituted with one or more
(a) halo,
(b) -OH,
(c) -CN,
(d) -CLIO alkyl,
(e) -C2- 10 alkenyl,
(f) -C2-10 alkynyl,
(g) -C3-I2 cycloalkyl,
(h) -O-Ci-io alkyl,
(i) -Cθ-6 alkyl-aryl, or
(j) -Cθ-6 alkyl-heteroaryl, wherein said alkyl, alkenyl, alkynyl, aryl and heteroaryl moiety is optionally substituted with one or more
(i) halo,
(UK)H5
(iii) -CN,
(W) -Ci-6 alkyl,
(v) -C2-6 alkenyl,
(vi) -OC 1-6 alkyl,
(vii) -C 1-6 haloalkyl,
(viiϊ) -Sθ2Ci-3 alkyl,
(x) -CO2R6,
(xii) -CONR6R6'5
(xiii) -NC(=0)-Co-3 alkyl-NR6R6\
(xiv) -NC(=O)R6, (XV) -NR6R6', and
(xvi) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen,
Q is -Ci _e alkylene, wherein said alkylene is optionally substituted with one or more:
(a) halo,
(b) -OH, (C) -CN,
(d) -Cl-IO alkyl
(e) -C3-12 cycloalkyl, (f) -O-Ci_10 alkyl, (g) aryl, and
(h) heteroaryl;
R3 is selected from the group consisting of (1) hydrogen, (2) -CLIO alkyl, (3) -C2-IO alkenyl, (4) -C2-10 alkynyl,
(5) -C3.12 cycloalkyl,
(6) -C3-12 cycloalkenyl,
(7) aryl, and
(8) heteroaryl, wherein said alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl or aryl or heteroaryl R3 moiety is optionally substituted with one or more
(a) halo,
(b) -OH,
(c) -CN,
(d) -Ci-io alkyl,
(e) -C2-10 alkenyl,
(f) -C3-12 cycloalkyl,
(g) -O-C3-12 cycloalkyl, Ch) -O-Ci-IO alkyl,
(i) -O-C3-12 heterocyclic, wherein said heterocyclic group has from 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen, sulfur and oxygen, (D aryl, (k) heteroaryl, (1) -NR6R6'5 and said alkyl, cycloalkyl, aryl and heteroaryl moiety is optionally substituted with one or more
(i) halo,
(U)-OH3
(Hi) -CN3
(iv) -Ci_io alkyl,
(v) -OCi_io alkyl, and
(vi) -NR6R6'
(vii) -C2-6 alkenyl,
(viii) -Ci _6 haloalkyl,
(ix) -SO2Ci-3 alkyl,
(xi) -CONR6R6,
(xii) NR5COR5'3 wherein R5' is selected from the same group as R5, or (xiii) NR7SO2R6, wherein R7 is selected from the group consisting of
(A) hydrogen,
(B) -Ci-io alkyl, and
(C) -C3-4 alkenyl; lected from the group consisting of
(1) hydrogen,
(2) -Ci-10 alkyl, and
(3) -C3-4 alkenyl, wherein said alkyl or alkenyl R4 group is optionally substituted with one or more
(a) halo,
(b) -OH
(c) -Ci_6 alkyl,
(d) -CN5 (e) -O-Ci-io alkyl,
(f) -NR8R95 wherein RB and R9 are selected from the group consisting of
(i) hydrogen, and (ii) -Ci_6 alkyl,
(g) -S(O)n-C 1-6 alkyl, wherein n is 0, 1 or 2,
(h) -C(=O)-R7, wherein R7 is selected from the group consisting of (i) hydrogen, (ϋ) OH5
(iii) -C 1-6 alkyl, and (iv) -OC 1-6 alkyl, and (v) aiyl;
R6 and R6' are selected from the group consisting of (1) hydrogen, (2) -Ci_6 alkyl, (3) -C3-7 cycloalkyl,
(4) -Cl-6 haloalkyl,
(5) -Co-6 alkyl-aryl5
(6) -Co-όalkyl-heteroaryl,
(7) halo, and
(8) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen, wherein said aryl or heteroaryl R5 moiety is optionally substituted with one or more
(a) halo,
(b) -Ci -6 alkyl,
(c) -O-Ci-6 alkyl, and
(d) -NO2; and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof. hi preferred embodiments of the compounds of formula (I), X is NR5, wherein R5 is preferably hydrogen. Alternatively, R5 is selected from the group consisting of optionally substituted
(1) -Ci-io alkyl,
(2) -C2-10 alkenyl,
(3) -C3-I2 cycloalkyl,
(4) -Cθ-6 alkyl-aryl, and
(5) -Co -6 alkyl-heteroaryl.
In preferred embodiments of the compounds of formula (I), R2 is phenyl, wherein the phenyl is optionally substituted with one or more (i) halo, (ii) -OH, (Ui) -CN, (iv) - Ci-io alkyl, and (v) phenyl optionally substituted with (A) halo, (BhOH, (C) -CN, (D) -Ci-6 alkyl, (E) -OCi -6 alkyl, (F) -SO2Ci.3 alkyl, (H) -NR5SO2Ci_3alkyl, (I) -CO2RS,
In preferred embodiments of the compounds of formula (I), Q is Ci .3 alkylene, most preferably -CH2-, and R3 is phenyl, wherein the phenyl is optionally substituted with one or more
(A) halo, (B)-OH, (C) -CN, (D) -Ci-io alkyl,
(E) -OCi-io alkyl, and
(F) phenyl, optionally substituted with
(i) -Ci-6 alkyl, (ii) -OCi_6 alkyl, (iii) NR5R5\
In preferred embodiments of the compounds of formula (T), R4 is— Cl -6 alkyl, most preferably methyl or ethyl.
Within the genus of compounds of formula (I), there is a sub-genus of hydantoin spiropiperidine compounds of formula (II)
wherein X, Q, R.2, Rβ and R4 are as defined above, and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.
In preferred embodiments of the compounds of formula (II), X is NR.5, and preferably R.5 is hydrogen. Alternatively, R5 is selected from the group consisting of optionally substituted
(1) -Ci-io alkyl,
(2) -C2-10 alkenyl,
(3) -C3-12 cycloalkyl,
(4) -Cθ-6 alkyl-aryl, and
(5) -Co-6 alkyl-heteroaryl.
In preferred embodiments of the compounds of formula (II), R.2 is phenyl, wherein the phenyl is optionally substituted with one or more (i) halo, (U) -OH5
(iii) -CN,
(iv) - Ci-IO alkyl, or
(v) phenyl, optionally substituted with (A) halo, (B)-OH, (C) -CN, (D) -Ci_6 alkyl, (E) -OCi-6 alkyl, (F) - SO2CL3 alkyl,
(H) -NR5S02Cl-3alkyl, (I) -CO2RS, (J) -CONR5R5'5 and (K) -NR5COR5\ In preferred embodiments of the compounds of formula (II), R4 is Cl -6 alkyl, most preferably methyl or ethyl.
Within the genus of compounds of formula (I), there is a sub-genus of cyclic urea compounds of formula (III) wherein Q, R2, R3 5 R4 and R5 are as defined above, and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.
In preferred embodiments of the compounds of formulas (HI), Q is Ci_3 alkylene, most preferably — CH2— , and R3 is phenyl, wherein the phenyl is optionally substituted with one or more
(A) halo,
(B)-OH,
(C) -CN5
(D)-Ci-io alkyl,
(E) -OCi-io alkyl, or
(F) phenyl, optionally substituted with (i) -Ci-6 alkyl, (ii) -OC i_6 alkyl, (iii) NR5R5\
In preferred embodiments of the compounds of formula (III), R4 is CI_6 alkyl, most preferably methyl or ethyl.
In preferred embodiments of the compounds of formula (III), R^ is selected from the group consisting of
(A) hydrogen,
(B) -Ci-io alkyl (preferably -Ci -4 alkyl),
(C) -C2-IO alkenyl (preferably -C2-4 alkenyl), or
(D) -Cθ-6 alkyl-aryl (preferably benzyl), or
(E) -Cθ-6 alkyl-heteroaryl (preferably -CH2-pyridyl).
Within the genus of compounds of formula (I), there is a sub-genus of cyclic carbamate compounds of formula (IV)
wherein Q, R2, R3 and R4 and R5 are as defined above, and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.
In preferred embodiments of the compounds of formula (IV), Q is Cl .3 alkyl ene, most preferably -CH2— , and R3 is phenyl, wherein the phenyl is optionally substituted with one or more
(A) halo,
(B)-OH,
(C) -CN,
(D) -Ci-io alkyl,
(E) -OCi-10 alkyl, or
(F) phenyl, optionally substituted with
(i) -C 1-6 alkyl,
(ii) -OCi -6 alkyl,
(iii) NR5R5\
In preferred embodiments of the compounds of formula (FV), R4 is Ci_6 alkyl, most preferably methyl or ethyl.
In preferred embodiments, the invention is directed to the following exemplary compounds of the invention: l-(3-fluorophenyl)-8-[(2'-methylbiphenyl-3-yl)methyl]-l,3,8-triazaspiro[4.5]decane-2?4-dione; ^-fluoro-l'-tS^S-isopropoxybenzy^-l^-dioxo-ljS^-triazaspiro^.SJdec-l-yl]-^^^- trimethylbiphenyl-4-sulfonamide;
4'-fluoro-2'- [8-(3 -isopropoxybenzyl)-2,4-dioxo- 1 ,3 , 8-triazaspiro [4.5] dec- 1 -yl] -N^N- dimethylbiphenyl-4-sulfonamide; dimethylbiphenyl-4-sulfonamide;
4'-fluoro-2'-[8-(3-isopropoxyben^l)-2,4-dioxo-3-propyl-l,3,8-triazaspiro[4.5]dec-l-yl]-iV>N- dimethylbiphenyl-4-sulfonamide;
4'-fluoro-2'-[8-(34sopropoxyben2yl)-2,4-dioxo-l,3,8-triazaspiro[4.5]dec-l-yl]-N!(iV- dimethylbiphenyl-4-sulfonamide; 2'-(8-ben2yl-2,4-dioxo-13,8-triazaspiro[4.5]dec-l-yl)-4'-fluoro-Λ^V-dimethylbiphenyl-4- sulfonamide;
4'-fluoro-2'-[8-(3-isopropoxybenzyl)-2,4-dioxo-l,3,8-triazaspiro[4.5]dec-l-yl]-iVr/V:,3- trimethylbiphenyl-4-carboxamide;
5-{4-fluoro-2-[8-(3-isopropoxybenzyl)-2,4-dioxo-1.3,8-triazaspiro[4.5]dec-l-yl]phenyl}-7V;Λ'- dimethylthiophene-2-sulfonamide;
(5i?,7S)-8-ben2yl-l-(2-bromo-5-fluorophenyl)-7-methyl-l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5i?,75)-l-(2-bromo-5-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3,8- triazaspiro[4.5]decane-2,4-dione;
(5^,75)-(5S,7R)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3,8- triazaspiro[4.5]decane-2,4-dione; l-(2-bromo-5-fluorophenyl)-8-(3-isopropoxybenz5d)-l,358-triazaspiro[4.5]decane-2,4-dione;
(5i?,75)-(5S,7R)-8-benzyl-l-(3-fluorophenyl)-7-methyl-l,3:r8-triazaspiro[4.5]decane-2,4-dione;
N-(3-{4-fluoro-2-[8-(3-isopropoxybenzyl)-2,4-dioxo-l,3»8-triazaspiro[4.5]dec-l-yl]phenyl}prop-
2-yn- 1 -yl)-iV-methylmethanesulfonamide ;
(5Λ,75)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3.8-triazaspiro[4.5]decane-2,4- dione;
(5i?,7S)-(5S.7R)-8-benzyl-l-[4-fluoro-4'-(methylsulfonyl)biphenyl-2-yl]-7-methyl-l,3,8- triazaspiro[4.5]decane-2,4-dione;
(5i?,7S)-l-(3-fluorophenyl)-7-methyl-8-[(2'-methylbiphenyl-3-yl)methyl]-l,3,8- triazaspiro[4.5]decane-2,4-dione; l-(3-fluorophenyl)-8-[(2'-me1hylbiphenyl-3-yl)methyl]-3-(pyridin-2-ylmethyl)-l53.8- triazaspiro [4.5] decan-2-one;
4'-fluoro-2'-[8-(3-isopropoxybenzyl)-2-oxo-l,3,8-triazaspiro[4.5]dec-l-yl]-ΛyV- dimethylbiphenyl-4-sulfonamide;
4'-fluoro-2'-[8-(3 -isopropoxybenzyl)-2-oxo-3-propyl- 1 ,3 ,8-triazaspiro[4.5]dec- 1 -yl]-ΛyV- dimethylbiphenyl-4-sulfonamide;
4'-fluoro-2'-[8-(3-isopropoxybenzyl)-3-methyl-2-oxo-l,3,8-triazaspiro[4.5]dec-l-yl]-AyV- dimethylbiphenyl-4-sulfonamide; l-[4-fluoro-4'-(methylsulfonyl)biphenyl-2-yl]-8-(3- isopropoxybenzyl)-l,3,8-triazaspiro[4.5]decan-2-one;(5/??75)-(5S,7R)-8-benzyl-l-(3- fluorophenyl)-7-methyl- 1 ,3 ,8-triazaspiro[4.5]decan-2-one; (5i?,75)-(5S,7R)- 1 -(3-fluorophenyl)-
7-methyl-8-(3 - { [( 1 R)- 1 -methylpropyl] oxy }benzyl)-3-pent-4-en- 1 -yl- 1 ,3 ,8-triazaspiro[4.5]decan-
2-one;
(5i?,75)-l-(3-fluorophenyl)-8-{3-[(li?)-2-methoxy-l-methylethoxy]benzyl}-7-methyl-l,3,8- triazaspiro[4.5]decan-2-one;(5R57S)-(5S,7R)-8-benzyl-l-[4-fluoro-4'-(methylsulfonyl)-l,l'- biphenyl-2-yl]-7-methyl-ls358-triazaspiro[4.5]decane-2,4-dione; (5RJS)-I -(3-fluorophenyl)-7-methyl-8-[(2'-methylbiphenyl-3-yl)methyl]- 1 ,3,8- triazaspiro[4.5]decane-2,4-dione; l-(3-fluorophenyl)-8-[(2'-metiiylbiρhenyl-3-yl)methyl]-3-(ρyridin-2-ylmethyl)-l53,8- triazaspiro[4.5]decan-2-one;
(5i-,75)-8-benzyl-l-(3-fluorophenyl)-7-methyl-3-oxa-l58-diazaspiro[4.5]decan-2-one; (5RJS)-I-
(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-[2-(4-methoxyphenyl)ethyl]-7-methyl-l,3,8- triazaspiro [4.5]decane-2,4-dione ;
(5R,7S)-3-(cyclohexylmethyl> 1 -(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l ,3,8- triazaspiro[4.5]decane-2,4-dione;
(5R.7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-(3-methoxybenzyl)-7-methyl-l,3,8- triazaspiro[4.5]decane-2,4-dione;
N-{2-[(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-1.3,8- triazaspiro[4.5]dec-3-yl]ethyl}benzamide;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxyben2yl)-7-methyl-3-[(l-methyl-lH-l,2,4-triazol-3- yl)methyl]-l53,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[2-(lH-pyrazol-l-yI)ethyl]- l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(5-methyl-l,2,4-oxadiazol-3- yl)methyl]-l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-3-(2-fluoroethyl)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l53,8- triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-3-(l,2-benzisoxazol-3-ylmethyl)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl- l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-3-[2-(2-fluorophenyl)-2-oxoethyl]-8-(3-isopropoxybenzyl)-7-methyl- l,358-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-3-[(l-benzyl-lH-l,2,4-triazol-5-yl)methylJ-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-
7-methyl-l,3,8-txiazaspiro[4.5]decane-2,4-dione;
(5R.7S)-l-(3-fluorophenyl)-3-(lH-ϊmidazol-2-ylmethyl)-8-(3-isopropoxybenzyl)-7-methyl-l>3,8- triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-3- { [5-(4-chlorophenyl)~ 1 ,3-oxazol-2-yl]methyl } - 1 -(3-fluorophenyl)-8-(3 - isoproρoxybenzyl)-7-methyl-l,3,8-triazasρiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(3-phenyl-l,2,4-oxadiazol-5- yl)methyl]-l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-3-[(5-cyclopropyl-l,3,4-thiadiazol-2-yl)methyl]-l-(3-fluorophenyl)-8-(3- isopropoxybenzyl)-7-methyl-l53,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxyben2yl)-7-methyl-3-[(5-methylisoxazol-3- yl)methyl] -1,3 »8-triazaspiro [4.5] decane-2,4-dione; (5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxyben2yl)-7-methyl-3-[(2-methyl-l,3-thiazol-4- yl)methyl]-l,3.8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-{[5-(4-methoxyphenyl)-l,2,4-oxadiazol-3- yl]methyl}-7-methyl-l,338-triazaspiro[4.5]decane-254-dione;
(5R,7S)-3-[(l,3-dimethyl-lH-pyrazol-5-yl)methyl]-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7- methyl- 1 ,3 ,8-triazaspiro [4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(5-phenylisoxazol-3-yl)methyl]- l,3,8-triazaspiro[4.5]decane-254-dione;
(5R,7S)-3-{[5-(3,4-dichlorophenyl)isoxazol-3-yl]methyl}-l-(3-fluorophenyl)-8-(3- isopropoxyben2yl)-7-methyl-l,358-triazaspiro[4.5]decane-2,4-dione;
3-[(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2.4-dioxo-l,3,8- triazaspiro[4.5]dec-3-yl]propanoic acid;
[(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxyben2yl)-7-raethyl-2,4-dioxo-l,3,8- triazaspiro[4.5]dec-3-yl]acetic acid;
N-(4-chlorophenyl)-2-[(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-
1 ,3 ,8-triazaspiro [4.5] dec-3 -yl] acetamide;
(5RJS)-l-(3-fluorophenyl)-8-(3-isopropoxybenzy])-7-methyl-3-(1.2,4-oxadiazol-3-ylmethyl)- l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxyben2yl)-7-methyl-3-(pyridin-2-ylmethyl)-l,3,8- triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l -(3-fluoroρhenyl)-3-(3-furylmethyl)-8-(3-isopropoxybenzyl)-7-methyl- 1 ,3 ,8- triazaspiro[4.5]decane-2,4-dione;
(5R57S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-(isoxazol-3-ylmethyl)-7-methyl-l,3J8- triazaspiro [4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-(l,3-oxazol-2-ylmethyl)-l,3,8- triazaspiro [4.5]decane-2,4-dione;
(5R57S)-l-(3-fluorophenyl)-8-(3-isopropoxyben2yl)-7-methyl-3-[(3-methyl-l,2,4-oxadiazol-5- yl)methyl]-l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-3-[(3-ethyl-l,2,4-oxadiazol-5-yl)methyl]-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7- methyl-l,358-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-(isoxazol-5-ylmethyl)-7-methyl-l,3,8- triazaspiro [4.5]decane-2,4-dione;
(SRJS^l-CS-fluoropheny^-S-CS-isopropoxybenzyO^-methyl-S-Kl-methyl-lH-l^^-triazol-S- yl)methyl]-l ,3,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8<3-isopropoxyberώyl)-7-methyl-3-[(l-methyl-lH-imidazol-2- y^methylj-l^^-triazaspiro^.SJdecane^^-dione; (5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(l-phenyl-lH-1.2.3-triazol-4- yl)methyl]-1.358-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)4-(3-fluorophenyl)-8<3-isopropoxybenzyl)-7-methyl-3-(pyrazin-2-ylmethyl)-l,3,8- triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-3-tert-butyl-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3,8- triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-(l-methyl-l-phenylethyl)-l,3,8- triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l<3-fluorophenyl)-8-(3-isopropoxybeii2yl)-7-methyl-3-(l53-thiazol-2-ylmethyl)-l,3,8- triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-(l,3-thia2θl-4-ylmethyl)-l,3,8- triazaspiro[4.5]decaBe-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-(2-methoxy-l5l-dimethylethyl)-7-methyl- ls3,8-triazaspϊro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-3-(2-furylmethyl)-8-(3-isopropoxyben2yl)-7-methyl-l,3,8- triazaspiro[4.5]decane-2,4-dione;
(5Λ,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-3-phenyl-l,3-diaza-8- azoniaspiro[4.5]decane trifluoroacetate;
(5R,7S)- 1 -(3 -fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3 -phenyl- 1 ,3,8- triazaspiro [4.5] decane-2,4-dione;
(5R,7S)-l,3-bis(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3:,8-triazaspiro[4.5]decane-
2,4-dione;
3-[(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-l,3:,8- triazaspiro[4.5]dec-3-yl]ben2onitrile;
(5R,7S)-3-[3-(dimeώylamino)phenyl]-l-(3-fluorophenyl)-8-(3-isopropoxyben2yl)-7-methyl-
1.358-triazaspiro[4.5]decane-2,4-dione;
(5R57S)-l-(3-fluorophenyl)-3-(lH-indol-5-yl)-8-(3-isopropoxyben2yl)-7-methyl-l,3,8- triazaspiro[4.5]decane-2,4-dione;
3-[(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxyben2yl)-7-methyl-2,4-dioxo-1.3:,8- triazaspiro[4.S]dec-3-yl]benzoic acid;
(5i?,7S)-l-(3-fluorophenyl)-8-(3-fiuylme1hyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-13 triazaspiro[4.5]decane-2!(4-dione;
N-[4-({(5R,7S)-l-(3-fluorophenyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-1.3,8- triazaspiro[4.5]dec-8-yl}methyl)phenyl]acetamide;
(5R,7S)-l<3-fluorophenyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-8-(pyridin-3-ylmethyl)- l,3,8-triazaspiro[4.5]decane-2,4-dione; (5R,7S)-8-benzyl-l-(3-fluorophenyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-l,3,S- triazaspiro [4.5] decane-2,4-dione;
(5R,7S)-8-(2-fluorobenzyl)-l-(3-fluorophenyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]- l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5RJS)-8-(cyclobutylmethyl)-l-(3-fluorophenyl)-7-me1hyl-3-[(5-methylisoxazol-3-yl)meth.yl]- l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-8-benzyl-3 - { [5-(3 ,4-dichlorophenyl)isoxazol-3 -yl]methyl } -1 -(3-fluorophenyl)-7-methyl- l,3j8-triazaspiro[4.5]decane-2,4-dione;
N_(4- { [(5RJS)- 1 -(3-fluorophenyl)-7-methyl-2,4-dioxo-l ,3 ,8-triazaspiro[4.5]dec-8- yl]methyl}phenyl)acetamide;
(5R,7S)-3-{[5-(354-dichlorophenyl)isoxazol-3-yl]methyl}-8-(2-fluorobenzyl)-l-(3-fluorophenyl)-
7-methyl- 1,3=8 -triazaspiro [4.5] decane-2,4-dione;
(5R,7S)-8-(cyclobutylmethyl)-3-{[5-(3,4-dichlorophenyl)isoxazol-3-yl]methyl}-l-(3- fluorophenyl)-7-methyl-l ,3»8-triazaspiro[4.5]decane-2,4-dione; C
3-[(5J?,7iS)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-l,358-triazaspiro[4.5]dec-l- yl]benzonϊtrile;
3-{(5i-J5)-8-(3-isopropoxybenzyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-l,3,8- triazaspiro[4.5]dec-l -yl}benzonitrile;
3-[(5R^7S)-3-[(5-cyclopropyl-13,4-thiadiazol-2-yl)niethyl]-8-(3-isopropoxybenzyl)-7-methyl-
2,4-dioxo-l,358-triazaspiro[4.5]dec-l-yl]benzonitrile;
3-[(5R,7S)-3-{[5-(3,4-dichlorophenyl)isoxazol-3-yl]methyl}-8-(3-isopropoxybenzyl)-7-methyl-
2,4-dioxo- 1 ,3 ,8-triazaspiro [4.5]dec- 1 -yl]benzonitrile;
3-{(5R,7S)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-3-[(l-phenyl-lH-l,2,3-triazol-4- yl)methyl] - 1 ,3,8-triazaspiro[4.5]dec- 1 -yl} benzonitrile;
3-{(5R.7S)-8-(3-isopropoxybenzyl)-3-[2-(4-methoxyphenyl)ethyl]-7-methyl-2,4-dioxo-l53,8- triazaspiro[4.5]dec-l -yl}benzonitrile;
N- {2-[(5R,7S)- 1 -(3-cyanophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-l ,3 ,8- triazaspiro[4.5]dec-3-yl]ethyl}benzamide;
3-((5R,7S)-8-(3-ϊsopropoxybenzyl)-3-{[5-(4-methoxyphenyl)isoxazol-3-yl]methyl}-7-methyl-
2,4-dioxo-l ,3,8-triazaspiro[4.5]dec-l-yl)benzonitrile; and
(5/J,7S)-l-(3-fluorophenyl)-7-methyl-8-[(2'-methylbiphenyl-3-yl)methyl]-3-[(5-methylisoxazol-
S-y^methy^-l.SjS-triazaspiro^.Sjdecane^^-dione;
and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.
The invention is also directed to methods of treating a patient (preferably a human) for diseases in which the β-secretase enzyme is involved, such as Alzheimer's disease, by administering a therapeutically effective amount of a spiropiperidine compound of any of the embodiments of formula (I), (IT), (HI), or (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention is also directed to methods of inhibiting BACEl enzyme activity, by administering a therapeutically effective amount of a spiropiperidine compound of any of the embodiments of formula (J), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, to a mammal or patient in need thereof. In another embodiment, the invention is directed to methods of inhibiting BACE2 enzyme activity, by administering a therapeutically effective amount of a spiropiperidine compound of any of the embodiments of formula (I), (II), (HI), or (TV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, to a mammal or patient in need thereof.
The invention is also directed to methods of treating a patient (preferably a human) for diseases in which the β-secretase enzyme is involved, such as Alzheimer's disease, by administering a therapeutically effective amount of a spiropiperidine compound of any of the embodiments of formula (I), (JI), (III), or (IV), or a pharmaceutically acceptable salt thereof, in combination with a P450 inhibitor, such as ritonavir, and a pharmaceutically acceptable carrier.
The invention is also directed to pharmaceutical compositions for the treatment of diseases in a patient (preferably a human) in which the β-secretase enzyme is involved, such as Alzheimer's Disease, which include a therapeutically effective amount of a compound of any of the embodiments of formula (I)5 (II), (ITl), or (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention is also directed to pharmaceutical compositions for the treatment of diseases in mammals (preferably humans) in which the β-secretase enzyme is involved, such as Alzheimer's Disease, which include a therapeutically effective amount of a compound of any of the embodiments of formula (I), (II), (JTL), or (TV), or a pharmaceutically acceptable salt thereof, together with a P450 inhibitor, such as ritonavir, and a pharmaceutically acceptable carrier.
The invention is further directed to a method for the manufacture of a medicament or a composition for inhibiting β-secretase enzyme activity in mammals (preferably humans) and animals comprising combining a therapeutically effective amount of a compound of any of the embodiments of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.
The invention is also directed to a method for the manufacture of a medicament or a composition for treating diseases in which the β-secretase enzyme is involved, such as Alzheimer's Disease, in mammals (preferably humans), comprising combining a therapeutically effective amount of compound of any of the embodiments of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier. The invention is also directed to a method for the manufacture of a medicament or a composition for treating diseases in which the β-secretase enzyme is involved, such as Alzheimer's Disease, in mammals (preferably humans), comprising combining a compound of any of the embodiments of formula (I), (II), (III), or (TV), or a pharmaceutically acceptable salt thereof, and a P450 inhibitor, such as ritonavir, with a pharmaceutically acceptable carrier.
As used herein, the term "alkyl," by itself or as part of another substituent, means a saturated straight or branched chain hydrocarbon radical having the number of carbon atoms designated (e.g., Ci_io alkyl means an alkyl group having from one to ten carbon atoms). Preferred alkyl groups for use in the invention are C\-β alkyl groups, having from one to six carbon atoms. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.
The term "Co alkyl," for example in the term "-Coalkyl-C6-12 aryl", refers to a bond.
As used herein, the term "alkylene," by itself or as part of another substituent, means a saturated straight or branched chain divalent hydrocarbon radical having the number of carbon atoms designated.
As used herein, the term "alkenyl," by itself or as part of another substituent, means a saturated straight chain divalent hydrocarbon radical having the number of carbon atoms designated.
As used herein, the term "alkenyl," by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical having a single carbon-carbon double bond and the number of carbon atoms designated (e.g., C2-10 alkenyl means an alkenyl group having from two to ten carbon atoms). Preferred alkenyl groups for use in the invention are C2-6 alkenyl groups, having from two to six carbon atoms. Exemplary alkenyl groups include ethenyl and propenyl.
As used herein, the term "alkynyl," by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical having a single carbon-carbon triple bond and the number of carbon atoms designated (e.g., C2-10 alkynyl means an alkynyl group having from two to ten carbon atoms). Preferred alkynyl groups for use in the invention are C2-6 alkynyl groups, having from two to six carbon atoms. Exemplary alkynyl groups include ethynyl and propynyl.
As used herein, the term "cycloalkyl," by itself or as part of another substituent, means a saturated cyclic hydrocarbon radical having the number of carbon atoms designated (e.g., C3.42 cycloalkyl means a cycloalkyl group having from three to twelve carbon atoms). The term cycloalkyl as used herein includes mono-, bi- and tricyclic saturated carbocycles, as well as bridged and fused ring carbocycles, such as spiro fused ring systems.
Preferred cycloalkyl groups for use in the invention are monocyclic C3-8 cycloalkyl groups, having from three to eight carbon atoms. Exemplary monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Exemplary bridged cycloalkyl groups include adamantly and norbornyl. Exemplary fused cycloalkyl groups include decahydronaphthalene.
As used herein, the term "heterocyclic," by itself or as part of another substituent. means a cycloalkyl group as defined above, in which one or more of the ring carbon atoms is replaced with a heteroatom (such as N or O). Suitable non-aromatic heterocyclic groups for use in the invention include piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl and imidazolildinyl. Preferred heterocyclic groups for use in the invention have four to eight ring atoms and a single nitrogen or oxygen heteroatom.
When a heterocyclic group as defined herein is substituted, the substituent may be bonded to a ring carbon atom of the heterocyclic group, or to a ring heteroatom (Le., a nitrogen, oxygen or sulfur), which has a valence which permits substitution. Preferably, the substituent is bonded to a ring carbon atom. Similarly, when a heterocyclic group is defined as a substituent herein, the point of attachment may be at a ring carbon atom of the heterocyclic group, or on a ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which has a valence which permits attachment. Preferably, the attachment is at a ring carbon atom.
As used herein, the term "aryl," by itself or as part of another substituent, means an aromatic or cyclic radical having the number of carbon atoms designated (e.g., C^- 10 81Yl means an aryl group having from six to ten carbons atoms). The term "aryl" includes multiple ring systems (such as fused ring systems) as well as single ring systems, and includes multiple ring systems wherein part of the molecule is aromatic and part is non-aromatic. The preferred single ring aryl group for use in the invention is phenyl. Preferred fused ring aryl groups include naphthyl, tetrahydronaphthyl and indanyl.
The term "halo" or "halogen" includes fluoro, chloro, bromo and iodo.
As used herein, the term "heteroaryl," by itself or as part of another substituent, means an aromatic cyclic group having at least one ring heteroatom (O, N or S). The term "heteroaryl" includes multiple ring systems as well as single ring systems. Preferred heteroaryl groups have from 5 to 12 ring atoms. Exemplary heteroaryl groups include pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, indazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl and benzoxazolyl. Preferred heteroaryl groups for use in the invention have 5 or 6 ring atoms. Exemplary groups include furanyl, thienyl and pyridyl.
When a heteroaryl group as defined herein is substituted, the substituent may be bonded to a ring carbon atom of the heteroaryl group, or on a ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which has a valence which permits substitution. Preferably, the substituent is bonded to a ring carbon atom. Similarly, when a heteroaryl group is defined as a substituent herein, the point of attachment may be at a ring carbon atom of the heteroaryl group, or on a ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which has a valence which permits attachment. Preferably, the attachment is at a ring carbon atom.
As used herein, the term "beta-secretase" or "β-secretase" refers to an enzyme that is sometimes known in the literature as "BACE", "BACEl" (see, e.g., Vassar et al., 1999, Science 286:735-741), or "BACE2" (see, e.g., Farzan et al., 2000, PNAS 97:9712-9717). BACEl is a 501 amino acid membrane-bound aspartic protease. BACEl has all the known functional properties and characteristics of β-secretase. BACE2, also called Asp-1 or memapsin-1, is a second member of the BACE family of membrane-bound aspartic proteases. See Roggo, Current Topics in Medicinal Chemistry, 2002, 2:359-370, for a further discussion of the differences between BACEl and BACE2.
The compounds of the invention are inhibitors of both the BACEl and BACE2 enzyme.
The compounds of the invention have at least two asymmetric centers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule.
For example, for the compounds of formula (I) and (IA), the 5-carbon and 7-carbon of the spiropiperidine ring are chiral. As a result, the compounds of formula (I) and (IA) may be present as two racemic diastereomers, or in four stereochemically pure forms.
The diastereomeric forms for compounds of formula (I) are depicted below, as diastereomers (I'), where the amine of the spiro center and the R4 group are cis to one another, and (I"), where the amine of the spiro center and the R.4 group are trans to one another.
(I1)
or
R^
(I")
When R4 is methyl or ethyl, the diastereomer (F) is the 5(S5R), 7(S5R) configuration, the diastereomer (I") is the 5(R,S),7(S,R) configuration.
Each of (F) and (1") may be present as a racemic mixture, or in one of two enantiomeric forms, as shown below with compound (F'), as compounds (I") and (F'*):
(I")
or
wherein when R4 is methyl or ethyl, the I" enantiomer is the 5(R),7(S) configuration and the F'* enantiomer is the 5(S),7(R) configuration.
Compounds of each of formulas (II), (III) and (TV) are also present in diastereomeric forms. For example, the diastereomeric forms for compounds of formula (II) are depicted below, as diastereomers (IF), where the amine of the spiro center and the R4 group are cis to one another, and (II"), where the amine of the spiro center and the R4 group are trans to one another.
or
When R4 is methyl or ethyl, the diastereomer (IIs) is the 5(S,R), 7(S3R) configuration, the diastereomer (II") is the 5(R,S),7(S,R) configuration.
Compounds with asymmetric centers give rise to eπantiomers (optical isomers), diastereomers (confϊgurational isomers) or both, and it is intended that all of the possible enantiomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention. The present invention is meant to encompass all such isomeric forms of these compounds.
Compounds described herein may contain one or more double bonds, and may thus give rise to cisltrans isomers as well as other configurational isomers. The present invention includes all such possible isomers as well as mixtures of such isomers.
Formulas (I)-(IV) are shown above without a definite stereochemistry at certain positions. The present invention includes all stereoisomers of formulas (I)-(IV)5 and pharmaceutically acceptable salts thereof.
The independent syntheses of the enantiomerically or diastereomerically enriched compounds, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers or diastereomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art.
Alternatively, any enantiomer or diastereomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
The compounds claimed in this invention can be prepared according to the following general procedure methods.
GENERIC SCHEME 1
Generic Scheme 1 depicts the formation of compounds of the invention. Combination of an isonitrile, an amine salt, a 4-piperidinone in which the nitrogen is bonded to a removable group P, and a cyanate salt are combined in an Ugi reaction similar to that described in I. Ugi, et.al. Angew. Chem. Int. Ed. Engl. I3 8-21, 1962 to give the intermediate iminohydantoin 1-1. The protecting group P may then be removed by a suitable method (HCl gas in EtOAc, for example, if the protecting group is BOC) to give the amine salt, which may then be derivatized with a suitable aldehyde through a reductive animation procedure similar to that described in J. March, Advanced Organic Chemistry, 3rd Ed. John Wiley and Sons, NY page 799. Hydrolysis of the iminohydantoin to the hydantoin then may take place under acidic conditions to give the product 1-4.
GENERIC SCHEME 2
A similar method is outlined in Generic Scheme 2. A suitable boronic ester reagent 2-2 may be prepared and coupled under organometallic catalysis to the iminohydantoin 2-4 to give the biphenyl intermediate 2-5, which is then hydrolyzed to the hydantoin 2-6 as described above.
GENERIC SCHEME 3
2NCO
Base
Generic Scheme 3 describes the synthesis of ortho biphenyl examples of type 3-3, 3-4 and 3-5, where R" may be H or Q (piperidine substituent). One of three methods, which vary on the entry point of the desired biphenyl, may be used to prepare analogs within this structural type. Method A starting from 3-1 from International Patent Application WO 2007/011833 involves first a Strecker reaction (similar to that described by J. Cossy in Synthesis 1995 11 1368-1370) with an o-haloaniline to give 3-1 A and its cis isomer which may be separated or taken on together to the next step. A Suzuki coupling and ring closure with chlorosulfonylisocyanate (similar to that described by R.Sarges et al. JOrg Chem 1982, 47, 4081-4085) gives 3-3. When P is a readily removable group, for example benzyl or CBZ, P can be removed with a suitable conditions, such as with a catalyst like Pd/C and H2, to give 3- 4. Further elaboration via alkylation or reductive amination gives examples of type 3-5. Method B uses a o- biphenylanilines initially in a Strecker reaction to give 3-2 followed by ring-closure and functional group manipulation as before. Method C starts from 3- IA and begins with ring- closure, then piperidine modification as needed and final Suzuki coupling to give additional examples of type 3-5.
GENERIC SCHEME 4
3-2 4-2 4-3
4-5
Generic Scheme 4 describes the synthesis of additional examples of the invention. Starting from 3-2 prepared as described above in Generic Scheme 3, the preparation begins with a ring closure with trichloroacetylisocyanate (similar to methods described in International Patent Application WO 2007/011833) to the intermediate iminohydantoin 4-2 which is then reacted with an amine to give the substituted iminohydantoin 4-3. The protecting group is removed with Pd(OH)2 and H2 to give 4-4. Further elaboration via alkylation or reductive amination gives examples of type 4-5. Optional Suzuki coupling to further elaborate QR3 can occur using Pd(O) followed by hydrolysis of the iminohydantoin to then give the hydantoin product 4-6. GENERIC SCHEME 5
mer
5-1 5-2 5-3
remove protecting group
A more direct route similar to Generic Scheme 4 that may be used is described in Generic Scheme 5. The mixture of Strecker products obtained in Scheme 4 may be cyclized in the presence of acid to give the hydantoin product 5-3 directly. The piperidine nitrogen protecting group may then be removed with a suitable method like hydrogenation and the nitrogen then derivatized by a suitable method, such as reductive amination or alkylation, using the methods described above, to give the products 5-5.
GENERIC SCHEME 6
6-1
Generic Scheme 6 depicts a variation on generic scheme 3 in which the hydantoin ring formation takes place first and then is followed with the palladium catalyzed coupling of an alkyne to yield compounds of the type 6-1. GENERIC SCHEME 7
7-5 7-6 7-7 7-8
Generic Scheme 7 outlines the preparation of cyclic ureas and carbamates covered by the scope of the invention. The product of the Strecker reaction, prepared in a manner similar to that described in J. Cossy, et.al. Synlett 1998, 251-252 described in Generic Scheme 3 above is reduced with a suitable reducing agent like DIBAL ,or NaBH45Or with a suitable catalyst like Raney Nickel or Rhodium and hydrogen to give the alcohol and amine products, which are cyclized with carbonyldiimidazole to give the cyclic urea or carbamate 7-4. The urea products may then be further functionalized by alkylation with alkyl halides and a suitable base like NaH to give products 7-5, or if QR3 is a removable group like benzyl, it may be removed via reduction with a suitable catalyst and H2 to give products 7-6 which may be alkylated to give products 7-7 and 7-8.
GENERIC SCHEME 8
WO 2007011833 alkyl halide RX heat base
Generic Scheme 8 outlines the preparation of compounds having a variety of substituents on the nitrogen of the hydantoin moiety. The iminohydantoin 8-1, the synthesis of which is described in International patent application WO2007/011833, is treated with aqueous acid and heat to afford the hydantoin 8-2. This material then may be treated with a base like potassium carbonate and an alkylating agent like an alkyl halide in a suitable solvent like DMF to give the alkylated product 8-3.
GENERIC SCHEME 9
Generic Scheme 9 outlines another method of preparing compounds having a variety of substituents on the nitrogen of the hydantoin moiety. In this method, the hydantoin 8-2 (described in Generic Scheme 8) is treated with a suitable alcohol under Mitsunobu reaction conditions, employing reagents like DEAD and triphenylphosphine to give the products 9-1.
GENERIC SCHEME 10
Generic Scheme 10 outlines another method of preparing compounds having a variety of substituents on the nitrogen of the hydantoin moiety. In this method, the hydantoin 8-2 (described in Generic Scheme 8) is treated with a suitable boronic acid under in the presence of a copper catalyst like copper acetate to give the N-aryl analogs 10-1.
GENERIC SCHEME 11
11-2
1L3
Generic Scheme 11 outlines another method of preparing compounds having different combinations of substituents on the nitrogen of the hydantoin and on the piperidine nitrogen, hi this method, the hydantoin 8-2 (described in Generic Scheme 8) is treated with a suitable base like potassium carbonate and an alkylating agent to give the N-alkylated intermediate 11-1. The benzyl group on the piperidine nitrogen is then removed with hydrogenation in the presence of a palladium catalyst like palladium hydroxide to give intermediate 11-2. The piperidine nitrogen is then treated with a suitable aldehyde under reductive amination conditions with a reagent like triacetoxyborohydride to give the product 11- 3. GENERIC SCHEME 12
12-2 12-3
Generic Scheme 12 outlines another method of preparing compounds having different combinations of substituents on the nitrogen of the hydantoin and on the piperidine nitrogen, and allows for the piperidine substituent to be incorporated last. In this method, the benzyl group on the hydantoin 8-2 (described in Generic Scheme 8) piperidine nitrogen is removed with hydrogenation in the presence of a palladium catalyst like palladium hydroxide to give intermediate 12-1. The piperidine nitrogen is then alkylated with a suitable alkylating agent to give intermediate 12-2, which is then treated with a suitable base like potassium carbonate and an alkylating agent to give the N-alkylated intermediate 12-3.
GENERIC SCHEME 13
Generic Scheme 13 outlines another method of preparing compounds covered in the scope of the invention, in particular those that possess a cyano substituent on the phenyl group. Acid hydrolysis of the iminohydantoin 13-1 (prepared in a manner similar to that described for example 11-6 in WO2007/011833 by using 3-cyanoaniline and condition A) using an aqueous acid like HCl is followed by hydrogenation with a catalyst like palladium hydroxide to give the intermediate 13-3. Alkylation of the piperidine nitrogen using a base like DIEA, then alkylation of the hydantoin nitrogen using a base like K2CO3 gives the products 13-5.
Where they are not themselves commercially available, the starting materials and reagents described in above Generic Schemes 1-13 may be obtained from commercially available precursors by means of well known synthetic procedures and the methods disclosed in the Examples herein. The term "substantially pure" means that the isolated material is at least 90% pure, and preferably 95% pure, and even more preferably 99% pure as assayed by analytical techniques known in the art.
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. The compounds of the invention may be mono, di or tris salts, depending on the number of acid functionalities present in the free base form of the compound. Free bases and salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine. diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholϊne, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylarnine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, trifluoroacetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, trifluoroacetic, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
The present invention is directed to the use of the compounds of formulas (I) to (IV) disclosed herein as.inhibitors of β-secretase enzyme activity or β-site amyloid precursor protein- cleaving enzyme ("BACE") activity, in a patient or subject such as a mammal in need of such inhibition, comprising the administration of an effective amount of the compound. The terms "β- secretase enzyme," "β-site amyloid precursor protein-cleaving enzyme," and "BACE" are used interchangeably in this specification. In addition to humans, a variety of other mammals can be treated according to the method of the present invention.
The compounds of the present invention have utility in treating, ameliorating, controlling or reducing the risk of Alzheimer's disease. For example, the compounds may be useful for the prevention of dementia of the Alzheimer's type, as well as for the treatment of early stage, intermediate stage or late stage dementia of the Alzheimer's type. The compounds may also be useful in treating, ameliorating, controlling or reducing the risk of diseases mediated by abnormal cleavage of amyloid precursor protein (also referred to as APP)5 and other conditions that may be treated or prevented by inhibition of β-secretase. Such conditions include mild cognitive impairment, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld- Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses. diabetes and atherosclerosis.
The subject or patient to whom the compounds of the present invention is administered is generally a human being, male or female, in whom inhibition of β-secretase enzyme activity is desired, but may also encompass other mammals, such as dogs, cats, mice, rats, cattle, horses, sheep, rabbits, monkeys, chimpanzees or other apes or primates, for which inhibition of β- secretase enzyme activity or treatment of the above noted disorders is desired.
The compounds of the present invention may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present invention have utility, where the combination of the drugs together are safer or more effective than either drug alone. Additionally, the compounds of the present invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the present invention. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with the compounds of the present invention. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to the compounds of the present invention. The combinations may be administered as part of a unit dosage form combination product, or as a kit or treatment protocol wherein one or more additional drugs are administered in separate dosage forms as part of a treatment regimen.
Examples of combinations of the compounds of the present invention with other drugs in either unit dose or kit form include combinations with anti-Alzheimer's agents, for example other beta-secretase inhibitors or gamma-secretase inhibitors; glycine transport inhibitors, tau phosphorylation inhibitors; blockers of Aβ oligomer formation; p25/CDK5 inhibitors; HMG- CoA reductase inhibitors; PPAR gamma agonists, such as pioglitazone and rosiglitazone; NK1/NK3 receptor antagonists; NSAID's including ibuprofen; vitamin E; anti-amyloid antibodies, including anti-amyloid humanized monoclonal antibodies; COX-2 inhibitors; anti- inflammatory compounds, such as (R)-flurbiprofen; CB-I receptor antagonists or CB-I receptor inverse agonists; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine and neramexane; NR2B antagonists; androgen receptor modulators; acetylcholinesterase inhibitors such as galantamine, rivastigmine, donepezil, and tacrine; mGluR5 modulators; growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine H3 antagonists; AMPA agonists; PDE IV inhibitors; GABAA inverse agonists; GABAA α 5 receptor ligands; GABAβ receptor ligands; potassium channel blockers; neuronal nicotinic agonists; P-450 inhibitors, such as ritonavir; or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention. The foregoing list of combinations is illustrative only and not intended to be limiting in any way.
The term "composition" as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. This term in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. hi general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation, hi the pharmaceutical composition the active compound, which is a compound of the invention (of formulas (I), (F), (II), (U'), (IH) and (III')), is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the invention and a pharmaceutically acceptable carrier.
The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in- water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compounds of the invention, may also be administered by controlled release means and/or delivery devices.
Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain a compound of the invention in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or algϊnic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
A tablet containing a composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, a compound of the invention in a free- flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about O.lmg to about 500 mg of the active ingredient and each cachet or capsule preferably containing from about O.lmg to about 500 mg of the compound of the invention.
Compositions for oral use may also be presented as hard gelatin Capsules wherein the compound of the invention is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the compound of the invention is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Other pharmaceutical compositions include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions, hi addition, oily suspensions may be formulated by suspending the compound of the invention in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension, or in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound of the invention, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can also be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art.
By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The terms "administration of or "administering a" compound should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individual's body in a therapeutically useful form and therapeutically useful amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, IM, or IP, and the like; transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.
The terms "effective amount" or "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
As used herein, the term "treatment" or "treating" means any administration of a compound of the invention and includes (1) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (2) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology). The term "controlling" includes preventing treating, eradicating, ameliorating or otherwise reducing the severity of the condition being controlled.
The compositions containing compounds of the invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The term "unit dosage form" is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person administering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages. Typical examples of unit dosage forms are tablets or capsules for oral administration, single dose vials for injection, or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.
The compositions containing compounds of the invention may conveniently be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person adminstering the drug to the patient. Such kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug. to the patient.
When treating, ameliorating, controlling or reducing the risk of Alzheimer's disease or other diseases for which compounds of the invention are indicated, generally satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.1 mg to about 100 mg per kg of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. The total daily dosage is from about 1.0 mg to about 2000 mg, preferably from about 0.1 mg to about 20 mg per kg of body weight. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
The amount of the compound of the invention that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may conveniently contain from about 0.005 mg to about 2.5 g of a compound of the invention, compounded with an appropriate and convenient amount of carrier material. Unit dosage forms will generally contain between from about 0.005 mg to about 1000 mg of the compound of the invention, typically 0.005 mg, 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg, administered once, twice or three times a day.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. The utility of the compounds in accordance with the present invention as inhibitors of β- secretase enzyme activity may be demonstrated by methodology known in the art. Enzyme inhibition is determined as follows.
ECL Assay: A homogeneous end point electrochemiluminescence (ECL) assay is performed using a biotinylated BACE substrate. The Km of the substrate is greater than 100 μM and can not be determined due to the limit of solubility of the substrate. A typical reaction contains approximately 0.1 nM enzyme, 0.25 μM of the substrate, and buffer (50 mM NaOAc, pH 4.5, 0.1 mg/ml BSA, 0.2% CHAPS, 15 mM EDTA and 1 mM deferoxamine) in a total reaction volume of 100 μl. The reaction proceeds for 30 min and is then stopped by the addition of 25 μL of 1 M Tris-HCl, pH 8.0. The resulting enzymatic product is assayed by adding a ruthenylated antibody which specifically recognizes the C-terminal residue of the product. Streptavidin coated magnetic beads are added into the solution and the samples are subjected to M-384 (Igen Inc., Gaithersburg. MD) analysis. Under these conditions, less than 10% of substrate is processed by BACE 1. The enzyme used in these studies is soluble (transmembrane domain and cytoplasmic extension excluded) human protein produced in a baculovirus expression system. To measure the inhibitory potency for compounds, 12 concentrations of inhibitors are prepared starting from 100 μM with three fold series dilution. Solutions of the inhibitor in DMSO are included in the reaction mixture (final DMSO concentration is 10 %). All experiments are conducted at rt using the standard reaction conditions described above. To determine the IC50 of the compound, a four parameter equation is used for curve fitting. The errors in reproducing the dissociation constants are typically less than two-fold.
In particular, the compounds of the following examples had activity in inhibiting the beta- secretase enzyme in the aforementioned assay, generally with an IC50 from about 1 nM to 200 μM. Such a result is indicative of the intrinsic activity of the compounds in use as inhibitors of beta-secretase enzyme activity.
Several methods for preparing the compounds of this invention are illustrated in the Schemes and Examples herein. Starting materials are made according to procedures known in the art or as illustrated herein. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.
INTERMEDIATES INTERMEDIATE I
Step 1: IA (1.03g, 0.00383mmol) was added to a stirred solution of dimethylamine hydrochloric acid (0.62Og, 2.0eq) and pyridine (1.55ml, 5.0eq) in DCM (15 ml) at O0C. After stirring for a while, the reaction mixture was allowed to warm up to rt and stirred overnight. The mixture was extracted with Et2O / saturated NaHCO3 aqueous solution twice, and Et2O / NaH2PO4 aqueous solution (pH = 3-4) twice, washed with brine twice, dried with MgSO4 and concentrated to afford
IB.
EI-MS m/z: 278, 280 (M + H)+
Step 2: IB (0.253g, 0.910mol), KOAc (0.268g, 3.0eq), ID (0.208g, 0.9eq) and PdCl2 (dppf) (0.074g, 0.1 eq) were added in a round bottom flask. Dry DMF (5ml) was then added under N2 protection. The resultant mixture was stirred for a while and put into an 800C oil bath. The reaction was followed by LCMS. Upon completion (2-4 h), reaction mixture was extracted with EtOAc / water three or four times, washed with brine twice. The resultant EtOAc solution was dried with MgSO4 and concentrated to afford crude Intermediate I. EI-MS m/z: 326 (M + H)+
INTERMEDIATE U
Step 1: IIA (4.874g, 0.0191mmol) was added to a stirred solution of Dimethylamine hydrochloric acid (2.33Og, 1.5eq) and pyridine (8.0ml, 5.2eq) in DCM (25 ml) at 00C. After stirring for a while, the reaction mixture was allowed to warm up to rt and the reaction was followed by LCMS. Upon completion (about 3h), the mixture was extracted with Et2O / saturated NaHCC>3 aqueous solution twice, and Et2O / NaH2Pθ4 aqueous solution (pH = 3-4) twice, washed with brine twice, dried with MgSO4 and concentrated to afford HB. EI-MS m/r. 266, 264 (M + H)+
Step 2: HB (3.21g, 0.0122mol), KOAc (3.58g, 3.0eq), HD (4.01g, 1.3eq) and PdCl2 (dppf) (0.993g, O.leq) were added in a round bottom flask. Dry DMF (60 ml) was then added under N2 protection. The resultant mixture was stirred for a while and put into an 800C oil bath. The reaction was followed by LCMS. Upon completion (2-4hrs), reaction mixture was extracted with EtOAc / water three or four times, washed with brine twice. The resultant EtOAc solution was dried with MgSO4 and concentrated to afford crude IIC. EI-MS m/r. 312 (M + H)+. Crude IIC (4.8Og, 0.0122mol), HE (3.01g, 1.3eq), Pd(PPh3)4(1.41g, O.leq), Na2CO3 (7.76g, 6.0eq), benzene (32ml), H2O (16ml) and EtOH (4ml) were mixed. The mixture was stirred and heated at 6O0C overnight. Once the mixture cooled down, in was mixture filtered. The solid was washed with water and Et2O. The organic phase was concentrated, redissolved in benzene with heating, precipitated with addition of hexane, washed with DCM and combine two batches of solid to afford Intermediate II. EI-MS m/r. 295 (M + H)+
INTERMEDIATE IH
HIA III
Step 1: To a stirred solution of 4-bromobenzenesulfonyl chloride (2.5 g, 10.0 mmol) in 50.0 mL
THF at O0C, was added 10.0 mL of 2M dimethylamine in THF. The reaction was stirred at rt for
3h, then quenched with water. The mixture was extracted three times with ethyl acetate, washed with water, IN HCl and brine. The solution was dried over magnesium sulfate, filtered, and concentrated to yield IHA as a white solid which was used for next reaction step without purification.
EI-MS m/r. 264.00 (M + H)+. Step 2: A mixture of IIIA (2.4 g5 9.0 mmol), bis(pinacolato)diboron (2.5 g, 10.0 mmol) and potassium phosphate (42.5 g, 20.0 mmol) in 50 mL DMF5 was purged with nitrogen gas, then added PdCl2(dppf) (4.0 g, 5.6 mmol). The solution was heated at 800C for 3h, cooled to it and quenched with water. The product was extracted three times with ethyl acetate, washed with water, saturated sodium bicarbonate and brine. The solution was dried over magnesium sulfate, filtered, concentrated then purified by silica gel column chromatography (EtO Ac-Hex 1 :1) to yield Intermediate BLI as an off-white solid. EI-MS m/z: 312.15 (M + H)+.
INTERMEDIATE IV
IVA IV
Step 1: To a stirred solution of 4-bromo-2-methylbenzoic acid (0.43 g, 2.0 mmol) in 10.0 mL THF, was added carbonyl diimidazole (0.356 g, 2.2 mmol). The resulting mixture was stirred at rt for 5 min, then added dimethylamine hydrochloride salt (0.179 g, 2.2 mmol), followed by triethylamine (0.56 mL, 4.0 mmol). The solution was stirred at rt for 3h, then quenched with water. The product was extracted three times with ethyl acetate, washed with water, saturated sodium bicarbonate, IN HCl and brine. The solution was dried over magnesium sulfate, filtered, and concentrated to yield IVA as a white solid which was used for next step without purification. EI-MS m/z: 244.0.5 (M + H)+.
Step 2: A mixture of IVA (0.376 g, 1.55 mmol), bis-(pinacolato)diboron (0.472 g, 1.86 mmol) and potassium acetate (0.761 g, 7.75 mmol) in 6.0 mL DMF, was purged with nitrogen gas, then added PdCl2(dppf) (340.0 mg, 0.465 mmol). The solution was heated at 800C for 3h, cooled to rt, then quenched with water. The product was extracted three times with ethyl acetate, washed with water, saturated sodium bicarbonate, brine, and dried over magnesium sulfate, filtered, concentrated and purified by silica gel column chromatography (EtO Ac-Hex 1:1) to yield Intemediate IV as an off-white solid. EI-MS m/z: 290.25 (M + H)+. INTERMEDIATE V
Step 1: To a stirred solution of 5-bromo-thiophene-2-sulfonyl chloride (1.05 g, 4.0 mmol) in 20.0 mL THF at O0C, was added 4.0 mL of 2M dimethylamine in THF. The solution was stirred at rt for 3 h, then quenched with water. The product was extracted three times with ethyl acetate, washed with water, IN HCl and brine. The solution was dried over magnesium sulfate, filtered, and concentrated to yield VA as a solid which was used for next reaction step without purification.
EI-MS m/z: 271.95 (M + H)+.
Step 2: A mixture of 2-bromo-5-fiuoro-phenylamine (380.0mg, 2.0mmol), bis(pinacolato)- diboron (559.0 mg, 2.2 mmol) and potassium acetate (981.0 mg, 10.0 mmol) in 10.0 mL DMF, was purged with nitrogen gas, then added PdCl2(dppf) (292.4.0 mg, 0.4 mmol). The solution was heated at 800C for 3h, cooled to rt. To the resulting reaction mixture was added 5.0 mL DMF, compound VA (810.0 mg, (3.0 mmol) and 5.0 mL of 2M K2CO3, purged with nitrogen gas, then added PdCl2(dppf) (292.4.0 mg, 0.4 mmol). The reaction mixture was heated at 800C for 3h, cooled to rt, and quenched with water. The product was extracted three times with ethyl acetate, washed with water, saturated sodium bicarbonate, brine, and dried over magnesium sulfate. The solution was filtered, concentrated and purified by silica gel column chromatography (EtO Ac- Hex 3:7) to yield Intermediate V as an oily residue. EI-MS m/z: 301.05 (M + H)+. INTERMEDIATE VI
Step 1 : l-[(2'-methylbiphenyl-3-yl)methyl]piperidin-4-one (Intemediate VI) To a suspension of 1 ;4-dioxa-8-azaspiro[4.5]decane (3.5 ml, 27.0 mmol) in 1 ,2-dichloroethane (200 ml) were added 2'-methylbiphenyl-3-carbaldehyde (5.0 g, 25.5 mmol) and acetic acid (1 ml). The reaction mixture was allowed to stir for 1 h at rt. Sodium triacetoxyborohydride (10.8 g, 51.0 mmol) was added to the reaction, and the mixture continued to stir for 18 h at rt. The reaction was quenched by the addition of a saturated sodium bicarbonate solution, diluted with dichloromethane, and allowed to stir vigorously for 1 h. The organic portion was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude oil was purified via flash chromatography (silica gel, 5% methanol/DCM) to yield 8-[2'- methylbiphenyl-3-yl)methyl]-l,4-dioxa-8-azaspiro[4.5]decane (54%). The material was dissolved in concentrated HCl (5.0 ml), stirred at rt for 12 h, and then at reflux for 2 days. The reaction was concentrated under vacuum and quenched with saturated sodium bicarbonate solution. The product was extracted with dichloromethane, and the organic portion was dried over sodium sulfate, filtered, and concentrated under vacuum. The material was purified via flash chromatography (silica gel, 0-5% methanol/dichloromethane) to yield l-[(2'- methylbiphenyl-3-yl)methyl]piperidin-4-one.
1H NMR (400 MHz, CDCl3) δ 7.39 (m, IH), 7.33 (m, 2H)5 7.26 (m, 5H), 3.68 (s, 2H), 2.78 (t, J = 6.0 Hz, 4H), 2.46 (t, J = 6.2 Hz5 4H), 2.28 (s, 3H). LCMS (M+H) 280.2. EXAMPLE l l-(3-fluorophenyl)-8-[(2'-methyl-l,l'-biphenyl-3-yl)methyl]-2,4-dioxo-l,3-diaza-8- azoniaspiro[4.5]decane trifluoroacetate
Step 1; tert-Butyl l-(3-fluorophenyl)-2-oxo-4-{[(trimethylsilyl)methyl]amino}-l,3,8- triazaspiro[4.5]dec-3-ene-8-carboxylate 1-1
To a 4 mL MeOH suspension of 2.Og (10.0 mmol) N-boc piperidinone and 1.35ml (9.5 mmol) trimethylsilyl methylisocyanide was added a solution of 1.02g (12.5 mmol) potassium isocyanate in 2.ImL H2O in one portion with stirring followed by 1.48g (10.0 mmol) 3-fluoroaniline hydrochloride in portions over 5 min. After stirring for 2h the reaction was treated with 250 ml CH2Cl2. The organic layer was washed with water (2x50ml), brine (lx50ml), dried over Na2SO4, filtered and concentrated to dryness under vacuum to give a crude oil. Purification by automated flash chromatography (0-5.5% MeOH in CH2Cl2 over 28min) afforded 1.04g tert- butyl l-(3-fluorophenyl)-2-oxo-4-{[(trimethylsilyl)methyl]amino}-l,3>8-triazaspiro[4.5]dec-3- ene-8-carboxylate as a white solid. Electrospray mass spectrum: M+H = 449.2
Step 2: tert-Butyl l-(3-fluorophenyl)-4-(methylamino)-2-oxo-l,3,8-triazaspiro[4.5]dec-3-ene-8- carboxylate 1-2
To a 50ml THF solution of 1.04g (2.41 mmol) tert-butyl l-(3-fluorophenyl)-2-oxo-4- { [(trimethylsilyl)methyl]amino}-l ,3,8-triazaspiro[4.5]dec-3-ene-8-carboxylate was added 3.6ImL (3.61 mmol) of a 1.0M tetrabutylammonium fluoride in THF solution over 5 min and the reaction warmed to 60 0C overnight. The reaction was concentrated to dryness under vacuum and the residue treated with 10OmL CH2CI2. The organic layer was washed with water (lx25mL), brine (lx25mL)5 dried over Na2SO4, filtered and concentrated to dryness under vacuum to give a crude oil. Purification by automated flash chromatography (0-7.5% MeOH in CH2Cl2 over 25 min) afforded 0.854g tert-butyl l-(3-fluorophenyl)-4-(methylamino)-2-oxo- 1 ,3,8-triazaspiro[4.5]dec-3-ene-8-carboxylate as a white solid. High resolution mass spec (FT/ICR): calc M+H = 377.1984, found 377.2010
Step 3 : 1 -(3-fluorophenyl)-4-methylammonio)-2-oxo- 1 ,3 -diaza-8-azoniaspiro[4.5]dec-3-ene Dihydrochloride 1-3
To a suspension of 834mg (2.21 mmol) tert-butyl l-(3-fluorophenyl)-4-(methylamino)-2-oxo- l,3.8-triazaspiro[4.5]dec-3-ene-8-carboxylate in 1OmL EtOAc at 00C was bubbled in HCl gas until the solvent was saturated. The reaction was stirred in the cold for 30m and concentrated under vacuum. The solid residue was reconcentrated to dryness (2x ethyl ether) and dried under high vacuum to give l-(3-fluorophenyl)-4-methylamino)-l,3,8-triazaspiro[4.5]dec-3-ene-2-one as its dihydrochloride salt as a fine white solid. High resolution mass spec (FT/ICR): calc M+H (free base) = 277.1459, found 277.1465
Step 4: l-(3-fluorophenyl)-8-[(2I-methyl-l,r-biphenyl-3-yl)methyl]-2s4-dioxo-1.3-diaza-8- azoniaspiro[4.5]decane trifluoroacetate (Example 1)
To a suspension of 35mg (0.100 mmol) l-(3-fluorophenyl)-4-methylammonio)-2-oxo-l,3-diaza- 8-azoniaspiro[4.5]dec-3-ene dichloride, 26uL (0.150 mmol) diisopropylethylamine, and 30mg (0.140 mmol) triacetoxy sodium borohydride in 1.OmL of DCE was added 20mg 2'-methyl-(l.l'- biphenyl)-3-carboxaldehyde (Oakwood Products Inc.). The resulting heterogeneous mixture was stirred at rt under a nitrogen atmosphere for 2h. The reaction mixture was treated with 2OuL saturated NaHCθ3 (aq) and concentrated under vacuum. Purification of the residue by preparative HPLC (5 -> 95% CH3CN/H2O over 30min, 0.05% added TFA, Cl 8 PRO YMC 20x150 mm) afforded l-(3-fluorophenyl)-4-(methylarnino)-8-[(2l-methyl-l,r-biphenyl-3- yl)methyI]-l,3,8-triazaspiro[4.5]dec-3-en-2-one (1-4, electrospray mass spectrum: M+H = 457.2) as a solution in aqueous acetonitrile containing 0.05% trifluoroacetic acid which was converted to ^(S-fluoropheny^-δ-^'-methyl-lJ'-biphenyl-S-yOmethyη-l.S.δ-triazaspiroμ.Sldecane^^- dione by heating this solution at 60 0C for 48h. Lyophilization afforded a white solid as the monofluoroacetic acid salt of the title compound.
1H NMR (CD3OD with l-4mg K2CO3 (s), 400 MHz): δ 7.48 (m, IH), 7.35 (m, IH), 7.21 (m, 7H), 7.10 (m, 3H), 3.58 (s, 2H), 2.86 (m, 2H), 2.75 (m, 2H), 2.19 (s, 3H), 2.02 (m, 2H)5 1.91 (m, 2H). High resolution mass spec (FT/ICR): calc M+H (free base) = 444.2082, found 444.2125 EXAMPLE 2
4'-fluoro-2'-[8-(3-isopropoxybenzyl)-2,4-dioxo-l,3,8-triazaspiro[4.5]dec-l-yl]-n,ns3- trimethylbiphenyl-4-sulfonamide
2
Step 1: Compound 2A (0.095Og, 0.166mmol, compound 15-1 in International Patent Publication WO2006/044497) and Intermediate I (0.131 g, 2.0eq), the palladium catalyst (AcO)2Pd(Cy2NH)2 (0.020Og, 0.65eq) and K3PO4 (0.034Og, 3.0eq) were weighed into a 1 dram vial. A magnetic stir bar was added, followed by absolute ethanol (ImL). The vial was capped, and placed to stir in a 80 deg C aluminum block over a hot plate. When the reaction showed black palladium precipitate (several hours), the reaction was cooled to room temperature. The reaction was then filtered through celite, and the resulting solution was purified by HPLC to afford Compound 2B. EI-MS m/z: 690 (M + H)+
Compound 2B (0.02Og, 0.0290mmol), IM aqueous HCl (5ml), and THF (ImI) were added. The resultant mixture was stirred and heated at 8O0C overnight. The mixture was extracted with EtOAc / saturated NaHCO3 aqueous solution twice, washed with brine twice, dried with MgSθ4, concentrated and purified by HPLC to afford Example 2. EI-MS m/z: 609 (M + H)+.
EXAMPLES 3-5
1 - {4'-[(dimethylamino)sulfonyl]-4-fluorobipheny l-2-yl } -8-(3 -isopropoxybenzyl)-2,4-dioxo- 1 ,3- diaza-8-azoniaspiro[4.5]decane trifluoroacetate (Example 3)
4l-fluoro-2'-[8-(3-isopropoxybenzyl)-3-methyl-2>4-dioxo-l,3,8-triazaspiro[4.5]dec-l-yl]-JV^V- dimethylbiphenyl-4-sulfonamide (Example 4)
4'-fluoro-2'-[8-(3-isopropoxybenzyl)-2,4-dioxo-3-propyl-l,3,8-triazaspiro[4.5]dec-l-yl]-iVyiV- dimethylbiphenyl-4-sulfonamide (Example 5) 3
Step 3: Intermediate II (2.8Og, 0.00951mol)3 Compound 3A (Example 14-4 of International Patent Publication WO2006/044497) 2.77g, 1.1 eq), HOAc (78ml) were mixed and heated at 6O0C until the solid was dissolved. The reaction mixture was cooled down. Trimethylsilyl cyanide (3.80ml, 3.0eq) added dropwise at 00C. The reaction mixture was then allowed to warm up to rt and stirred overnight. The reaction was quenched with ammonium hydroxide in ice until the pH reached 10, then filtered. The solid was washed with water and Et2θ and dried under vacuum at 4O0C to afford compound 3B. EI-MS m/z: 295 (M + H)+.
Step 4: To the solution of Compound 3B (0.25Og, 0.454mmol) in DCM (3ml), was added ' dropwise at O0C chlorosulfonyl isocyanate (0.043ml, 1.1 eq). The mixture was stirred at rt for 35 min. Water (ImI) was then added. The reaction mixture was stirred for 1 h. IM aqueous HCl (9ml)and THF (l-2ml) were added and the resulting mixture was stirred and heated at 600C for 2 days. The mixture was extracted with EtOAc / saturated NaHCOa aqueous solution twice, washed with brine twice, dried with MgSO4, concentrated and purified by HPLC to afford Example 3. ■ EI-MS m/z: 595 (M + H)+
Step 5: To a stirred solution of Example 3 (0.02Og, 0.0336mmol) in DMF (1.5ml), was added NaH (60% dispersion in mineral oil) (0.013g, 10eq) at 00C. MeI (0.0020ml, l.Oeq) was then added. The reaction was allowed to warm up to rt and stirred for another 30 min, then quenched with saturated aqueous NH4Cl solution, extracted with Et2θ twice, washed with brine twice, dried with MgSO4, concentrated and purified by preparative TLC (0.8% 2M ammonia in MeOH/DCM) to afford Example 4. EI-MS m/z: 609 (M + H)+
Step 6: To a stirred solution of Example 3 (0.020g, 0.0336mmol) in DMF (1.5ml), was added NaH (60% dispersion in mineral oil) (0.013g, 10eq) at O0C. "PrI (0.0048ml, l.Oeq) was then added. The reaction mixture was warmed to rt and stirred for another 30 min. The reaction was quenched with saturated aqueous NH4Cl solution, extracted with Et2O twice, washed with brine twice, dried with MgSO4, concentrated and purified by preparative TLC (0.5% 2M ammonia in MeOH/DCM) to give Example 5. EI-MS m/z: 637 (M + H)+.
EXAMPLE 6
1 - {4'-[(dimethylamino)sulfonyl]-4-fluorobiphenyl-2-yl } -8 -(3 -isopropoxybenzyl)-2,4-dioxo- 1 ,3 - diaza-8-azoniaspiro[4.5]decane trifluoroacetate (Alternative preparation of Example 3).
6A EXAMPLE 6
4-(cyclohexylamino)-l-{4'-[(dimethylamino)sulfonyl]-4-fluorobiphenyl-2-yl}-8-(3- isopropoxybenzyl)-2-oxo-l,3-diaza-8-azoniaspiro[4.5]dec-3-ene trifluoroacetate (6A TFA salt, prepared as previously described in International Patent Publication W 02006/044497, Example 15-2) , 96.0mg, 0.122mmol, l.Oequiv) was dissolved into a mixture acetonitrile (2 mL) and water (1 mL) in a vial. TFA (0.10 mL) was added, and the reaction was heated in an aluminum block at 90° C for 3 h, until LCMS indicated disappearance of the starting material (M + H)+ ion. The reaction was then cooled to rt, and submitted directly for purification by reverse phase HPLC in acetonitrile/water, providing the desired spirocyclic Example 6 (27.9mg, 32%) as its TFA salt. EI-MS m/z: 595 (M + H)+.
EXAMPLE 7 8-benzyl-l - {4'-[(dimethylamino)sulfonyl]-4-fluorobiphenyl-2-yl } -2,4-dioxo-l ,3-diaza-8- azoniaspiro[4.5]decane trifluoroacetate
EXAMPLE 7
Step 3: To a solution of the amine 7 A (Example 15-46 in International Patent Publication WO2006/044497) (84.7 mg, 0.2mmol) in 2.OmL DMF5 was added potassium carbonate (30.4 mg, 0.22 mmol), followed by benzyl bromide (27.0 μL, 0.22mmol). The solution was heated at 800C for 15h, cooled to rt then quenched with water. The product was extracted three times with ethyl acetate, washed with water and brine. The solution was dried over magnesium sulfate, filtered, concentrated and purified by silica gel column chromatography (100% EtOAc) to provide 7B. EI-MS m/z: 513.15 (M + H)+.
Step 4: A mixture of 7B (50.2 mg, 0.1 mmol), Intermediate HI (62.2 mg, 0.2 mmol), potassium phosphate (43.6 mg, 0.2 mmol), and in 2.0 mL ethanol, was purged with nitrogen gas, then added DAPCy (58.6 mg, 0.1 mmol). The solution was heated at 800C for overnight, or until complete disappearance of compound 7B(monitored by LCMS). The crude was purified by preparative HPLC to provide 7C as an amine-TFA salt. EI-MS m/z: 618.30 (M + H)+.
Step 5: A suspension of compound 7C (10.0 mg, 0.014 mmol) in 1.0 mL of IM HCl was heated at 800C overnight. The final product was purified by preparative HPLC to provide Example 7 as an amine-TFA salt. 1HNMR (CD3OD): δ ppm 0.94 (d, J=14.67 Hz, 1 H), 1.45 (m, 1 H,) 1.94 (m, 1 H), 2.38 (d, J=14.67 Hz5 1 H), 2.69 (s, 6 H)5 3.14 (d, J=13.21 Hz, 1 H), 3.51 (m, 3 H) 4.24 (s, 2 H), 7.43 (m, 6 H), 7.65 (d, J=7.83 Hz, 3 H), 7.83 (d, J=8.31 Hz, 2 H). EI-MS m/z: 537.15 (M + H)+.
EXAMPLE 8 l-{4'-[(dimethylamino)carbonyl]-4-fluoro-3'-methylbiphenyl-2-yl}-8-(3-isopropoxybenzyl)-2,4- dioxo-1 ,3-diaza-8-azoniaspiro[4.5]decane trifluoroacetate
Step 1 : A mixture of 8 A (compound 2 A from Example 2) (60.0 mg, 0.1 mmol), Intemediate IV (31.9 mg, 0.11 mmol), potassium phosphate (42.5 mg, 0.2 mmol), and in 2.0 mL ethanol, was purged with nitrogen gas, then added DAPCy (29.0 mg, 0.05 mmol). The solution was heated at 800C until complete disappearance of compound 8A (monitored by LCMS). The crude reaction mixture was purified by preparative HPLC to provide 8B as the amine-TFA salt. EI-MS m/z: 654.30 (M + H)+.
Step 4: A suspension of compound 8B (10.0 mg, 0.013 mmol) in 1.0 mL of IM HCl was heated at 800C overnight. The final product was purified by preparative HPLC to provide Example 8 as an amine-TFA salt.
1H NMR (CD3OD): δ ppm 1.01 (d, j=14.67 Hz, 1 H), 1.29 (s, 6 H), 1.45 (m, 14.18 Hz, 1 H),
1.97 (t, J=13.94 Hz, 1 H), 2.26 (s, 3 H), 2.36 (d5 J=I 5.65 Hz5 1 H)5 2.88 (s, 3 H), 3.13 (s5 4 H)5
3.47 (m, 2 H)5 3.60 (t5 J=12.72 Hz, 1 H), 4.20 (s, 2 H), 4.60 (s, 1 H), 6.97 (m, 3 H), 7.32 (m, 6
H), 7.60 (s, 1 H).
EI-MS m/z: 573.3 (M + H)+. EXAMPLE 9 l-(2-{5-[(dimethylamino)sulfonyl]-2-thienyl}-5-fluorophenyl)-8-(3-isopropoxyben2yl)-2,4- dioxo- 1 ,3-diaza-8-azoniaspiro[4.5]decane trifluoroacetate
Step 1: To an ice-cold solution of l-(3-isopropoxybenzyl)-piperidin-4-one (Example 14-4 of International Patent Publication WO2006/044497) 79.5 mg, 0.3 mraol) and lntemediate V (99.4 mg, 0.33 mmol) in glacial acetic acid (1.5 mL), was added slowly trimethylsilyl cyanide (44.0 μL, 0.33 mmol). The reaction mixture was kept at O0C for 5 min then rt for 30 min. The resulting mixture was quenched with ammonium hydroxide in ice until the pH reached 10 then extracted two times with dichloromethane. The combined dichloromethane extract was washed with brine, dried over magnesium sulfate and concentrated. The product was purified by silica gel column (40% ethylacetate/60% hexane) to provide 9A as an oil residue. EI-MS m/z: 557.25 (M + H)+.
Step 4: To an ice cold solution of 9A (108.4 mg, 0.19 mmol) in 1.0 mL chloroform, was added dropwise chlorosulfonyl isocyanate (49.7μL, 0.22 mmol) and stirred at rt for 30 min, then added 0.50 mL of water. The reaction mixture was stirred for another Ih at rt then added to an ice cold aqueous solution of H2S (156.1 mgNa2S + 4.0 mL H2O + 1.0 mL acetic acid), which was prepared right before use. The resulting reaction was stirred at rt for 24 h then hydrolyzed with 1.0 mL IN HCl at 800C over a 5h period. The reaction mixture was made basic with saturated sodium bicarbonate solution, and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated. The final product was purified by preparative HPLC to provide Example 9 as an amine-TFA salt. 1H NMR (CD3OD): δ ppm 1.30 (d, J=5.38 Hz, 6 H), 1.42 (d3 J=14.67 Hz5 1 H)5 1.63 (m, 1 H), 2.05 (m, 1 H), 2.44 (d, J=14.67 Hz, 1 H), 3.25 (s, 1 H), 3.47 (d, J=13.21 Hz5 1 H)5 3.62 (m, 2 H), 4.24 (s, 2 H), 4.61 (m, 1 H)5 6.98 (m, 3 H), 7.33 (m, 3 H), 7.45 (t, J=8.07 Hz, 1 H), 7.59 (s, 1 H),
7.79 (m, 1 H).
EI-MS m/z: 601.20 (M + H)+.
The following examples were prepared starting with the l-(3-isopropoxybenzyl)- piperidin-4-one, (Example 14-4, of International Patent Publication WO2006/044497), 1-benzyl- 2-methylpiperidin-4-one or l-(3-isopropoxybenzyl)-2-methylpiperidin-4-one (Intermediate I and II in International Patent Application WO 2007/011833, filed July 14, 2006) using a procedure similar to that described for Examples 9 and 10, except that after treatment with chlorosulfonylisocyanate and water the reaction was treated with HCl to give the hydantoin product. In some instances, the racemic mixture was resolved via chiral HPLC to give the final enantiomerically pure product. Example 16 was made from palladium catalyzed coupling of N- methyl-iV-prop-2-yn-l-ylmethanesulfonarnide (J. Med. Chem. 1988, 31 577-582) and example 14 using Pd(tBu3P)2 , CuI, DIEA in dioxane.
EXAMPLE 16 A: ALTERNATIVE PREPARATION OF EXAMPLE 16
Step 1: (5R5 7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3,8- triazaspiro[4.5]decane-254-dione (Example 16*)
To the solution of the bisphosphate salt of (5R, 7S)-4-(cyclohexylamino)-l-(3- fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl- 1 ,358-triazaspiro [4.5]dec-3-ene- 2-one (Intermediate VII, International patent application WO2007/011833, 10.0 g, 14.2 mmol) in CH3CN (25 mL) was added aqueous HCl (4 N, 25 mL). The reaction mixture was purged with nitrogen, sealed and heated at 90°C in a 350 mL sealed tube. After two days, the reaction mixture was concentrated, and partitioned between EtOAc and aqueous saturated NaHCθ3. The EtOAc extract was washed with brine, dried using anhydrous Na2SO4, concentrated under reduced pressure to obtain the desired product. HRMS (M+l) = 426.28
EXAMPLE 17
(5R,7S)-(5S,7R)-8-benzyl- 1 -[4-fluoro-4'-(methylsulfonyl)- 1 , 1 '-biphenyl-2-yl] -7-methyl- 1,3,8- triazaspiro[4.5]decane-2,4-dione
EXAMPLE 17
Step 1: 17B: (5R,7S)-(5S,7R)-l-benzyl-4-(4'-bromo-4-fluoro-l,lt-biphenyl-2-yl)-2- methylpiperidine-4-carbonitrile
To a solution of l-benzyl-2-methylpiperidin-4-one (Intemediate I in International Patent Application WO 2007/011833 4.30 g, 21.2 mmol) in acetic acid (20 ml) at O0C were added 2- bromo-4-fluoroanillne (4.02 g, 21.2 mmol) and trimethylsilyl cyanide (2.82 ml, 21.2 mmol). The reaction was allowed to warm to rt and was then heated to 7O0C. After 48 h, additional trimethylsilyl cyanide (2.82 ml, 21.2 mmol) was added to the reaction. The reaction was heated to 7O0C and allowed to stir for 7 days. The reaction was poured onto cold ammonium hydroxide and crushed ice and adjusted to pH 10. The product was extracted with dichloromethane (3x50 ml), washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude oil was purified via flash chromatography (silica, 0-20% EtOAc/hexanes) to isolate both (5R, 7R)-(5S7S) and (5R,7S)-(5S,7R)-l-benzyl-4-(4l-bromo-4-fluoro-l,l'-biphenyl-2-yl)-2- methylpiperidine-4-carbonitrile.
1H NMR (400 MHz, CDCl3) δ 7.39 (dd, J = 8.8, 6.0 Hz, IH), 7.26 (m, 5H), 6.84 (dd, J = 10.8, 2.8 Hz, IH), 6.44 (td, J = 8.2, 2.4 Hz, IH), 4.48 (s, IH), 4.09 (d, J == 14.4 Hz, IH), 3.08 (d5 J = 13.6 Hz, IH), 2.64 (m, IH)5 2.55 (m, IH), 2.32 (dt, J = 14.0, 2.8 Hz, IH), 2.27 (dt, J = 11.5, 2.9 Hz, IH), 2.08 (m, 3H), 1.22 (d, J = 6.4 Hz, 3H). LCMS (M+H) 401.9.
Step 2: 17C: (5R,7S)-(5S,7R)-l-benzyl-4-[4-fluoro-4'-(methylsulfonyl)-l,lI-biphenyl-2-yl]-2- methylpiperidine-4-carbonitrile
To a solution of (5R,7S)-(5S,7R)-l-benzyl-4-(4'-bromo-4-fluoro-l,l'-biphenyl-2-yl)-2- methylpiperidine-4-carbonitrile (17B, 100 mg, 0.25 mmol) in DMF/water (80/20 v/v, 0.6 ml) under a nitrogen atmosphere were added 4-(methanesulfonyl)phenylboronic acid (74.7 mg, 0.37 mmol), tris(456-dim.ethyl-3-sulfanatophenyl)phospMne trisodium salt hydrate (24.4 mg, 0.04 mmol), palladium(II) acetate (2.8 mg, 0.01 mmol), and diisopropylamine (0.1 ml, 0.75 mmol). The reaction mixture was vortexed briefly to dissolve the catalyst and was stirred at 400C for 18 h. The reaction was purified via reverse phase chromatography to yield (5R,7S)-(5S,7R)-1- benzyl-4-[4-fluoro-4'-(methylsulfonyl)- 1 , 1 l-biphenyl-2-yl]-2-methylpiperidine-4-carbonitrile. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.0 Hz5 2H)S 7.47 (d, J = 8.0 Hz, 2H), 7.32 (m, 3H), 7.25 (m, 2H), 7.04 (dd, J = 8.4, 6.4 Hz, IH)9 6.85 (dd, J =- 11.2, 2.4 Hz, IH), 6.62 (td, J = 8.2, 2.3 Hz, IH), 3.97 (d, J = 13.6 Hz, IH), 3.68 (s, IH), 3.23 (d, J = 13.2 Hz, IH), 3.11 (s, 3H), 2.62 (dt, J = 12.3, 3.1 Hz, IH), 2.24 (m, 3H), 2.10 (dt, J = 12.9, 3.7 Hz, IH), 1.99 (m, 2H), 1.20 (d, J = 5.6 Hz, 3H). LCMS (M+H) 478.0.
Step 3: Example 17: (SRJSXSS^RVS-benzyl-l-^-fluoro-^-^ethylsulfonyO-l^'-biphenyl^- yl]-7-methyl-l,3,8-triazaspiro[4.5]decane-2,4-dione
To a solution of (5R,7S)-(5S,7R)-l-benzyl-4-[4-fluoro-4'-(methylsulfonyl)-l,r-biphenyl-2-yl]-2- methylpiperidine-4-carbonitrile (17C, 19.0 mg, 0.04 mmol) in dichloromethane (0.5 ml) was added chlorosulfonyl isocyaπate (5.7 mg, 0.04 mmol) portion-wise. The reaction was allowed to stir at rt for 1 h and then concentrated. The residue was dissolved in IN HCl, and the reaction was heated at 1000C for 1 h. The reaction mixture was cooled to rt and adjusted to pH 5.5 by the addition of 5N NaOH. The crude material was purified via reverse phase chromatography to yield (5R57S),(5S,7R)-8-benzyl-l-[4-fluoro-4'-(methylsulfonyl)-l,r-biphenyl-2-yl]-7-methyl- 1 ,3 ,8-triazaspiro [4.5] decane-2 ,4-dione.
1H NMR (400 MHz5 CDCl3) δ 8.00 (d, J = 8.4 Hz, 1.1H), 7.92 (d, J = 8.4 Hz5 0.9H), 7.61 (d, J = 8.4 Hz, 1.1H)5 7.52 (d, J = 8.4 Hz, 0.9H)5 7.37 (dd, J = 8.8, 6.0 Hz, 0.7H), 7.26 (m, 5H), 7.09 (m, ' 2.3H), 3.80 (d, J = 9.6 Hz, 0.4H), 3.76 (d, J = 14.8 Hz, 0.6H), 3.64 (s5 IH), 3.15 (d, J = 14.0 Hz, 0.4H), 3.12 (s, 1.8H), 3.08 (s, 1.2H), 3.02 (d, J = 13.6 Hz, 0.6H)5 2.56 (m, 0.8H), 2.08 (m, 0.9H), 1.60 (t, J = 13.2 Hz5 1.4H), 1.49 (m, 0.6H), 1.13 (d, J = 5.6 Hz, 1.3H)5 0.78 (d, J - 6.4 Hz5 1.7H), 0.55 (m, IH). HRMS (ES, M+H), calcd. for C28H28FN3O4S: 522.1858, found: 522.1844.
EXAMPLE 18
(5R,7S)-l-(3-fluorophenyl)-7-methyl-8-[(2'-methylbiphenyl-3-yl)methyl]-l,3,8- triazaspiro[4.5]decane-2,4-dione
EXAMPLE 18 18E 18D Step 1: Benzyl (5JR,7S)-l-(3-fluorophenyl)-7-methyl-4-(methylamino)-2-oxo-l,3,8- triazaspiro[4.5]dec-3-ene-8-carboxylate (18B)
To a flask containing benzyl (52?,7ιS)-4-arnino-l-(3-fluorophenyl)-7-methyl-2-oxo-l,3.,8- triazaspiro[4.5]dec-3-ene-8-carboxylate (343 mg, 0.86 mmol; described in International Patent Application WO 2007/011833 Example 115 Intermediate 11-6) was added methylamine (2.0 M THF, 4.3 mL, 8.6 mmol). The vessel was sealed and placed in a 70 0C oil bath and stirred overnight. The reaction was diluted with aqueous NaHCO3 and extracted with EtOAc (three times). The combined organic layers were washed with brine, isolated and subsequently dried over Na2SO4. Evaporation of solvent and further drying under vacuum gave crude product that was used in the next step. LCMS [M+H] = 411.2
Step 2: (5i-,7S)-l-(3-fluorophenyl)-7-methyl-4-(methylammo)-l,358-triazaspiro[4.5]dec-3-en-2- one (18C).
The product from step 1 above, benzyl (5i?,7ιS)-l-(3-fluorophenyl)-7-methyl-4-(methylamino)-2- oxo-l,3,8-triazaspiro[4.5]dec-3-ene-8-carboxylate (370 mg, 0.86 mmol) was dissolved in 8 mL MeOH. The solvent was degassed with a nitrogen flow for 10 min. and Pd(OH)2 (30 mg, 20% wt. Pd) added. The mixture was purged with a hydrogen balloon for 10 min. and then maintained under atmospheric hydrogen at rt overnight with stirring. The reaction was then filtered over Celite, the cake rinsed with EtOAc and the filtrate concentrated to dryness under reduced pressure to give after drying under vacuum the product as a white solid. LCMS [M+H] = 291.2
Step 3: (5R,7S)-l-(3-fluorophenyl)-8-(3-iodobenzyl)-7-methyl-4-(methylamino)-l5358- triazaspiro[4.5]dec-3-en-2-one (18D). .
(5RJS)- 1 -(3-fluorophenyl)-7-methyl-4-(methylamino)-l 5358-triazaspiro[4.5]dec-3-en-2-one (250 mg, 0.86 mmol) from step 2 above was dissolved in DMSO (8.0 mL). The flask was charged with K2CO3 (594 mg, 4.30 mmol) and 3-iodo-benzylbromide (255 mg, 0.86 mmol). The mixture was then sealed with a septum and placed in 50 0C oil bath and allowed to stir overnight. The mixture was diluted with water and extracted with EtOAc (three times). The combined organic layers were washed with aqueous LiCl (three times), followed by brine and then dried over Na2SO4. Solvent removal under reduced pressure gave crude product. Purification over silica via automated flash chromatography (0 to 20 % MeOH/CHjCb over 20 min.) gave after solvent removal the product as a white solid: LCMS [M+H] = 507.3 Step 4: (5i?JS)-l<3-fluorophenyl)-7-methyl-4-(methylainino)-8-[(2l-inethylbiphenyl-3- yl)methyl]-l,3,8-triazaspiro[4.5]dec-3-en-2-one (18E)
A Biotage microwave vial was charged with intermediate (5R,7S)-l-(3-fluorophenyl)-8-(3- iodobenzyl)-7-methyl-4-(methylamino)-l,3>8-triazaspiro[4.5]dec-3-en-2-one (60 mg, 0.118 mmol) from step 3 above, PdC^dppf (4.3 mg, 0.01 mmol) and 2-tolylboronic acid (21 mg, 0.15 mmol). The vial was sealed and put under a nitrogen atmosphere. To the solids was added aqueous 1.5M K.2CO3 (0.24 mL, 0.35 mmol) and degassed THF (0.7 mL). The mixture was briefly vortexed and heated in an Optimizer microwave for 5 min. at 120 0C. The reaction enclosure was removed and the reaction diluted with EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and the solvent removed under reduce pressure. Purification over silica via automated flash chromatography (0 to 10% MeOH/CHaCk) afforded, after solvent removal under reduced pressure, the product as a white solid: LCMS [M+H] = 471.2
Step 5: (5JR,75)-l-(3-fluoroρhenyl)-7-methyl-8-[(2'-methylbiphenyl-3-yl)methyl]-l,3,8- triazaspiro[4.5]decane-2,4-dione (Example 18).
In a scintillation vial (5i?,75)-l-(3-fluorophenyl)-7-methyl-4-(methylamino)-8-[(2'- methylbiphenyl-3-yl)methyl]-l,3,8-triazaspiro[4.5]dec-3-en-2-one (15 mg, 0.031 mmol) from step 4 above was dissolved in THF (1.0 mL). To this IN HCL (3 mL) was added and the mixture sealed and heated in a 80 0C oil bath until disappearance of starting material as evident by LCMS. The mixture was then concentrated to dryness and purified by RP-HPLC using a TFA buffered solvent system to give, after lyophilization, Example 18 as a TFA salt. 1HNMR (400 MHz, CD3OD3 Hz): δ 7.5-7.1 (m, 12H), 4.35 (AB, J=15.2 Hz, 2H), 3.46 (m, IH), 2.90 (m, IH), 2.63 (m, IH), 2.53-2.30 (m, 4H)5 2.21 (s, 3H), 1.56 (d, J =6.0 Hz, 3H). LCMS [M+H] = 458.0;
EXAMPLE 19
1 -(3-fluorophenyl)-8-[(2' -methylbiphenyl-3-yl)methyl]-3-(pyridin-2-ylmethyl)- 1 ,3 ,8- triazaspiro[4.5]decan-2-one
Step 1 : 4-[(3-fluorophenyl)amino]-l-[(2'-methylbiphenyl-3-yl)methyl]piperidine-4-carbonitrile (19A)
4-[(3-fluorophenyl)amino]-l-[(2'-methylbiphenyl-3-yl)methyl]piperidine-4-carbonitrile was prepared from l-[(2'-methylbiphenyl-3-yl)methyl]piperidin-4-one (intermediate VI, 1.3 g, 4.5 mmol), 3-fluoroaniline (0.4 ml, 4.5 mmol), and trimethylsϊlyl cyanide (0.6 ml, 4.5 mmol) in a manner similar to 17B from Example 17. LCMS (M+H) 400.1.
Step 2 : 4-(aminomethyl)-N-(3 -fluorophenyl)- 1 - [(2 ' -methylbiphenyl-3 -yl)methyl]piperidin-4- amine (19B)
To a suspension of 4-[(3-fluorophenyl)amino]-l-[(2'-methylbiphenyl-3-yl)methyl]piperidine-4- carbonitrile (19A, 700 mg, 1.75 mmol) in ethanol (50 ml) was added a small amount of Raney Nickel (in water). The reaction was placed under an atmosphere of hydrogen and allowed to stir at rt for 5 days. The reaction was filtered, the filtrate was concentrated under vacuum, and the crude material was purified via reverse phase chromatography. The product was dissolved in dichloromethane, neutralized with excess potassium carbonate, and filtered. The filtrate was concentrated under vacuum to yield 4-(aminomethyl)-N-(3 -fluorophenyl)- 1- [(2' -methylbiphenyl- 3 -yl)methyl] piperidin-4-amine.
1HNMR (400 MHz, DMSO) δ 7.38 (m, IH)5 7.22 (m. 6H), 7.00 (m, IH)5 6.51 (m5 2H)5 6.28 (m5 IH)5 5.24 (s, IH)5 4.11 (m, IH)5 3.49 (s, 2H)5 3.15 (m5 2H)5 2.71 (s, 2H)5 2.29 (t, J = 9.8 Hz, 2H)5 2.21 (s, 3H)5 2.03 (m, IH)5 1.91 (d, J = 13.6 Hz, 2H)5 1.56 (t, J = 10.5 Hz5 2H). LCMS (M+H) 404.3.
Step 3: l-(3-fluorophenyl)-8-[(2'-methylbiphenyl-3-yl)methyl]-l,3,8-triazaspiro[4.5]decan-2- one (19C)
1 -(3 -fluorophenyl)-8- [(2' -methy lbiphenyl-3 -yl)methyl]- 1 ,3 ,8-triazaspiro [4.5] decan-2-one was prepared from 4-(aminomethyl)-N-(3-fluorophenyl)-l-[(2'-methylbiphenyl-3- yl)methyl]piperidin-4-amine (19B5 265 mg, 0.66 mmol), N,N'-carbonyldiimidazole (107 mg, 0.66 mmol)5 and triethylamine (140 μl, 0.99 mmol) in a manner similar to Example 20. LCMS (M+H) 430.2.
Step 4: 1 -(3-fluorophenyl)-8-[(2'-methylbiphenyl-3-yl)methyl]-3-(pyridin-2-ylmethyl)-l ,3,8- triazaspiro[4.5]decan-2-one (Example 22) l-(3-fluorophenyl)-8-[(2'-methylbiphenyl-3-yl)methyl]-3-(pyridin-2-ylmethyl)-l,3,8- triazaspiro[4.5]decan-2-one was prepared from l-(3-fluorophenyl)-8-[(2'-methylbiphenyl-3- yl)methyl]-l,3,8-triazaspiro[4.5]decan-2-one (19C5 30 mg5 0.07 mmol) and 2- (bromomethyl)pyridine hydrobromide (12 mg, 0.07 mmol) in a manner similar to Example 21. 1H NMR (400 MHz5 CDCl3) δ 8.57 (d, J = 4.8 Hz5 IH)5 7.69 (td5 J = 7.6, 1.7 Hz5 IH)5 7.33 (m, 3H)5 7.21 (m, 8H)5 7.00 (m, 2H)5 6.93 (d, J = 9.8, 2.1, IH)5 4.60 (s5 2H), 3.46 (s, 2H)7 3.38 (s, 2H), 2.85 (d5 J = 11.7 Hz, 2H)5 2.22 (S5 3H), 1.99 (t, J = 11.4 Hz, 2H)5 1.84 (td, J = 12.5, 3.8 Hz5 2H)5 1.70 (d, J = 12.1 Hz5 2H). LCMS (M+H) 521.4.
EXAMPLES 20-22
4'-fluoro-2'-[8-(3-isopropoxybenzyl)-2-oxo-l53,8-triazaspiro[4.5]dec-l-yl]-Nr/V- dimethylbiphenyl-4-sulfonamide (Example 20)
1 - { 4'- [(dimethylamino)sulfonyl] -4-fluorobiphenyl-2-yl} -8 -(3-isopropoxybenzyl)-2-oxo-3-propyl~ l,3-diaza-8-azoniaspiro[4.5]decane trifluoroacetate (Example 21) l-{4'-[(dimethylamino)sulfonyl]-4-fluorobiphenyl-2-yl}-8-(3-isopropoxybenzyl)-3-methyl-2- oxo-l53-diaza-8-azoniaspiro[4.5]decane trifluoroacetate (Example 22)
2OA 2OB E=XAMPLE 20
NaH Rl
Compound 2OA (Scheme 35 intermediate 3-B, 4.11Og5 0.00746mol), Rh/ Al2O3 (1.35Og) and 6N ammonia in MeOH (50ml) were mixed together. The mixture was allowed to be hydrogenated in the Parr shaker at 45 psi overnight. Filtrated with celite and concentrated to afford crude Compound 2OB. EI-MS m/z: 555 (M + H)+ at 1.50.
Crude Compound 2OB (0.31Og, 0.559mmol), carbonyldiimidazole (0.136g, 1.5eq) and DCM (2ml) were mixed and heated at 55°C overnight. The mixture was concentrated and purified by preparative HPLC to afford Example 20. EI-MS m/z: 581 (M + H)+ at 1.63.
To a stirred solution of Example 21 (0.025g, 0.043 lmmol) in DMF (1.5ml), was added NaH (60% dispersion in mineral oil) (0.013g, 10eq) at 00C. MeI (0.0026ml, l.Oeq) was then added. The reaction was allowed to warm to rt and stirred for another 30 min before being quenched with saturated aqueous NH4Cl solution. The mixture was extracted with Et2O twice and the combined organic extracts were washed with brine twice, dried with MgSO4, and purified by preparative HPLC to afford Example 21. EI-MS m/z: 595 (M + H)+ at 1.68.
To a stirred solution of Example 24 (0.025g5 0.0431mmol) in DMF (1.5ml), was added NaH (60% dispersion in mineral oil) (0.013g, 10eq) at O0C. MeI (0.0026ml, l.Oeq) was then added and the reaction was allowed to warm to rt and stirred for another 30 min. The reaction was quenched with saturated aqueous NH4Cl solution, extracted with Et2O twice, washed with brine twice, dried with MgSθ4, concentrated and purified by preparative HPLC to afford Example 22. EI-MS m/z: 623 (M + H)+ at 1.74.
The following examples were prepared starting withl-(3-isopropoxybenzyl)-piperidin-4- one , (Example 14-4, in International Patent Application WO 2006/044497), l-benzyl-2- methylpiperidin-4-one (Intermediate I in International Patent Application WO 2007/011833) or l-(3-5ec-butoxybenzyl)-2-methylpiρeridin-4-one (also from International Patent Application WO 2007/011833) using a procedure similar to that described for Examples 3 and 20. The 3-fluoro- 2-(4-methyanesulfonylphenyl)analine used for Example 23 was prepared in a manner similar to that described for Intermediate V. For Examples 25-27, the benzyl group of Example 24 was removed with catalyst and hydrogen, and the piperidine alkylated with l-(chloromethyl)-3- isopropoxybenzene (International Patent Application WO 2007/011833 Example 11, Intermediate 11-lOC), l-(chloromethyl)-3-{[(li?)-l-methylpropyl]oxy}benzene (above patent, Intermediate 111), or l-(chloromethyl)-3-[(li?)-2-methoxy-l-methylethoxy]benzene, which was made in a manner similar to that described for the above Intermediate III.
EXAMPLE 28
8-benzyl-l-(3-fluorophenyl)-7-methyl-2-oxo-3-oxa-l-aza-8-azoniaspiro[4.5]decane trifluoroacetate
Step 1: l-benzyl-4-[(3-fluorophenyl)amino]-2-methylpiperidine-4-carbonitrile To a mixture of l-benzyl-2-methylpiperidin-4-one (Intermediate I, from International Patent Application WO 2007/011833, filed July 14, 2006, 3.0 g, 14.8 mmol) in HOAc (15 mL) was added 3-fluoroaniline (1.64 g, 14.8 mmol) and TMSCN(1.97 mL, 14.8 mmol). After stirring at rt overnight the reaction mixture was poured into 15 mL NH4OH and 15g ice. The pH of the solution was adjusted to pH = 8 by additional NH4OH. The resulting solution was extracted with CHCI3 three times, dried with MgSO4 and concentrated. LRMS (M+l) = 324
Step 2 : 1 -benzyl-4-[(3-fluorophenyl)amino] -2-methylpiperidine-4-carbonitrile
(2Rs4R)-l-benzyl-4-[(3-fluorophenyl)amino]-2-methylpiperidine-4-carbonitrile (4.77 g, 14.8 mmol) was dissolved in MeOH (10OmL) and added to a sealed tube. After heating overnight the reaction mixture was concentrated and purified on a silica gel cartridge (5% EtOAc/ hexanes to 30% EtOAc / hexanes) to afford the desired product. The rest of the mixture was heated again and chromatographed to afford the desired product. LRMS (M+l) =324
Step 3 : 1 -benzyl-4- [(3 -fluorophenyl)amino] -2-methylpiperidin-4-yl } methanol
To a solution of (2S,4R)-l-ben2yl-4-[(3-fluorophenyl)anύno]-2-methylpiperidine-4-carbonitrile (1.29 g, 3.99 mmol) in methylene chloride added DIBAL in cyclohexane (10.88 mL, 11.97 mmol). After stirring for 3h the reaction was quenched with water then concentrated H2SO4. Additional DCM was added and the solution was warmed to rt. The layers were separated and the aqueous layer was made basic by the addition of NaOH. The aqueous phase was extracted with DCM three times, dried with MgSO4 and concentrated. To the resulting oil was added dry MeOH (10 mL) and excess NaBH4 (0.754 g, 19.9 mmol) at O0C. After stirring for 72h the reaction was quenched with sodium bicarbonate solution and diluted with DCM. The layers were separated and extracted with DCM to afford a mixture of the desired alcohol product as well as amine resulting from incomplete hydrolysis of the imine precursor. The mixture of both intermediates was used directly in the next reaction. LRMS (M+l) =329
Step 4: 8-benzyl-l-(3-fluorophenyl)-7-methyl-2-oxo-3-oxa-l-aza-8-azoniaspiro[4.5]decane trifluoroacetate
Carbonyldiimidazole (0.851 g, 5.25 mmol) was added to a solution of {(2S,4R)-l-benzyl-4-[(3- fluorophenyl)amino]-2-methylpiperidin-4-yl} methanol (0.862 g, 2.63 mmol) in THF. The mixture was cooled to 00C and NaH (2.63 mmol) was added. After 4h at rt, the reaction was quenched with NH4CI and made slightly basic with IM NaOH. The basic solution was extracted with DCM three times, dried with MgSO4 and concentrated under vacuum. Purification by reverse phase HPLC afforded the desired compound.
1H NMR (CD3OD): δ 7.55 - 7.06 (m, 9H), 4.50 (m, IH), 4.25 (m, 2H), 3.80 (m, IH), 3.48 -
3.12 (m, 3H), 2.65 (m, 2H), 2.09 (m, 2H)3 1.50 (m, 3H).
HRMS = 355.18-
EXAMPLE 29
-(5JR,75)-l-(3-fluorophenyI)-8-(3-isopropoxybenzyI)-3-[2-(4- methoxyphenyI)ethyI]-7-methyl-2,4-dioxo-l,3-diiaza-8-azoniaspiro[4.5]decane trifluoroacetate
Step 1: (5JR,75)-l-(3-fluorophenyI)-8-(3-isopropoxybenzyI)-3-[2-(4- methoxyphenyl)ethyl]-7-methyl-2,4-dioxo-13-diaza-8-azoniaspiroI4.5]decane trifluoro acetateExample 29
To a mixture of l-(2-chloroethyl)-4-methoxybenzene (0.034 g, 0.20 mmol) and anhydrous K2CO3 (0.042 g, 0.30 mmol) was added a solution of (5R, 7S)-l-(3- fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3,8-tria2aspiro[4.5]decane-2>4- dione (Example 16, 0.043 g, 0.10 mmol) in anhydrous DMF (1 mL). After stirring at 500C for 16 hours, the reaction was cooled and quenched with aqueous NH4Cl. The resulting mixture was extracted with EtOAc (two times) and the EtOAc extract was concentrated under reduced pressure. The crude material was purified by reverse phase preparative HPLC to afford the desired compound as a TFA salt. For NMR analysis, the sample was dissolved in CDCI3 and converted to free base by NH3 vapor.
1H NMR (600 MHz3 CDCl3): δ /.36 (q, J=5.97 Hz, IH), 7.12-7.14 (m, 4H), 6.94 (dd, J=8.02 Hz, IH), 6.85-6.86 (m, 3H)5 6.70-6.73 (m, 3H), 4.51 (rn, IH), 3.80- 3.82 (m, 3H)5 3.78 (s, 3H), 2.95 (t, J=7.56 Hz, 2H), 2.86 (d, J=14.0 Hz3 IH), 2.57 (m, IH), 2.17-2.18 (m, 2H), 2.01 (t, J=14.0 Hz, IH), 1.68-1.73 (m, 3H), 1.31 (d, ./=6.37 Hz3 6H), 1.06 (d, J=5.73 Hz, 3H). LRMS (M+l) = 560.29
The following examples were prepared using a procedure similar to that described for Example 29. In some instances, the compound was isolated as the TFA salt after chromatography, and in some cases the compound was then isolated as the free base by extraction from a suitable aqueous base like bicarbonate solution with a suitable organic solvent like methylene chloride. The free base could then be transformed to the hydrochloride salt by treatment with an ether solution of HCl. Examples 29-21 and 29-22 were prepared using the esterified form of the alkylating agent, and the ester product was then saponified to the acid.
EXAMPLE 30
-(5i?,7-S)-l-(3-fluorophenyl)-3-(3-furylmethyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo- 1 ,3-diaza-8-azoniaspiro [4.5] decane trifluoroacetate
Step 1 : (SjRJ^-l-CS-fluorophenyO-S-CS-furylmethy^-S-CS-isopropoxybenzyl)- 7-methyl-2,4-dioxo-l,3-diaza-8-azoniaspiro[4.5]decane trifluoroacetate
Example 30
To a mixture of (5R, 7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl- l53,8-triazaspiro[4.5]decane-254-dione (Example 16. 0.043 g, 0.10 mmol), 3- furylmethanol (0.020 g, 0.20 mmol), and PS-PPh3 (0.093 g, 0.20 mmol, resin loading 2.15 mmol/g) in anhydrous THF (1 mL) was added DEAD (0.035 g, 0.20 mmol). After stirring at room temperature for 16 hours, the reaction was diluted with THF, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by reverse phase preparative HPLC to afford the desired compound as a TFA salt. For NMR analysis, the sample was dissolved in CD3OD and converted to free base by NH3 vapor.
1H NMR (600 MHz, CD3OD): δ 7.51 (s, IH), 7.43 (m, IH), 7.38 (m, IH), 7.11- 7.15 (m, 4H), 6.75 (dd, J=8.00 Hz, 2.52 Hz, IH), 6.64-6.66 (m, 2H), 6.43 (m, IH), 4.55 (s, 2H), 4.53 (m, IH), 3.76 (d, J=12.9 Hz, IH), 3.14 (d, J=12.9 Hz, IH), 2.59 (m, IH), 2.22-2.19 (m, 2H), 2.02-2.08 (m, 3H), 1.84 (m, IH), 1.29 (d, J=6.11 Hz, 6H), 1.15 (d, J=6.17 Hz, 3H). LRMS (M+l) = 506.25
The following examples were prepared using a procedure similar to that described for Example 30. In some instances, the compound was isolated as the TFA salt after chromatography, and in some cases the compound was then isolated as the free base by extraction from a suitable aqueous base like bicarbonate solution with a suitable organic solvent like methylene chloride. The free base could then be transformed to the hydrochloride salt by treatment with an ether solution of HCl.
Example 31
(SΛjVi^-l-CS-fluoropheny^-S-CS-isopropoxybeπzy^-T-methyl-l^-dioxo-S-phenyl-l^-diaza- 8-azoniaspiro[4.5]decane trifluoroacetate
Step 1 : (51^7,S)-l-(3-fluorophenyl)-8-(3-isopropoxybeiizyl)-7-methyl-2,4- dioxo-3-phenyl-l,3-diaza-8-azoniaspiro[4.5]decane trifluoroacetate Example Ii
A solution of (5R, 7S)-l-(3-fmorophenyl)-8-(3-isopropoxybenzyl)-7-methyl- l,3,8-triazaspiro[4.5]decane-2,4-dione (Example 16, 0.043 g, 0.10 mmol), phenylboronic acid (0.048 g, 0.40 mmol), and copper(II) acetate (0.004 g, 0.020 mmol) in MeOH (1 mL) was prepared. After heating at 70°C for 16 hours, it was cooled to room temperature, and then diluted with MeOH (2 mL). QuadraPure TU resin was added to the reaction mixture. After stirring for 30 minutes at room temperature, the reaction mixture was filtered, and the filtrate was concentrated. The crude material was partitioned between EtOAc (two times) and aqueous NH4Cl. The EtOAc extract was concentrated under reduced pressure, and the crude material was purified by reverse phase preparative HPLC to afford the desired compound as a TFA salt.
1H NMR (400 MHz, CD3OD): δ 7.41-7.52 (m, 5H), 7.25-7.37 (m, 4H), 7.13-7.17 (m, IH), 7.04 (d, J=7.79 Hz, IH), 6.77 (s, 2H), 4.58-4.61 (m, IH), 4.25-4.34 (m, 2H), 3.47 (m, IH), 2.92 (m, IH), 2.76-2.79 (m, IH), 2.65 (m, IH)5 2.40-2.54 (m, 4H), 1.59 (d, 7=5.86 Hz, 3H), 1.34 (d, J=4.76 Hz, 6H). LRMS (M+l) = 502.25
The following examples were prepared using a procedure similar to that described for Example 31. In some instances, the compound was isolated as the TFA salt after chromatography, and in some cases the compound was then isolated as the free base by extraction from a suitable aqueous base like bicarbonate solution with a suitable organic solvent like methylene chloride. The free base could then be transformed to the hydrochloride salt by treatment with an ether solution of HCl.
EXAMPLE 32
(5Λ,75)-l-(3-fluorophenyI)-8-(3-furylmethyl)-7-methyl-3-[(S-methylisoxazol-3-yl)methyI]- 2,4-dioxo-l,3-diaza-8-azoniaspiro[4.5]decane trfifluoroacetate
Step 1. (5R,7S)- 1 -(3 -fluorophenyl)-8 -(3 -isopropoxybenzyl)-7-methyl-3 - [(5 -methylisoxazol-3 - yl)methyl]- 1 ,3,8-triazaspiro[4.5]decane-2,4-dione 32^A
To a mixture of 3-(chloromethyl)-5-methylisoxazole ( 1.12 g, 8.53 mmol) and anhydrous K2CO3 ( 3.22 g, 23.27 mmol) was added a solution Of(SR, 7S)-l-(3-fluorophenyl)-8-(3- isopropoxybenzyl)-7-methyl-l,3,8-triazaspiro[4.5]decane-2,4-dione (Example 16, 3.3 g, 7.76 mmol) in 15 mL DMF . After stirring at 60 0C for 16 hours, the reaction was cooled and filtered and concentrated under reduced pressure. The crude material was chromatographed on a silica gel cartridge using a gradient of DCM / MeOH 100:0 to 50:50. The resulting fractions were concentrated under reduced pressure to a foam which was placed under high vacuum for 16 hrs. LRMS (M+!) = 521.1
Step 2. (55,71S)-l-(3-fluorophenyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-l ,3,8- triazaspiro[4.5]decane-2,4-dione 32-B To (5JR,75)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(5-methylisoxazol-3- yl)memyl]-l,3.8-triazaspiro[4.5]decane-2,4-dione 32- A (1.4 g, 2.69 mmol) in a round bottom flask was added 1.25 M HCl in MeOH (30 ml). The solution was swirled and the solvent was removed under reduced pressure to leave the HCl salt of 32-1. To this HCl salt in MeOH (30 rnL), under nitrogen, was added palladium hydroxide 20 wt % on carbon (0.38 g, 0.27 mmol). The flask was fitted with a three way valve. The flask was evacuated with high vacuum until the solvent bubbled then nitrogen was flushed in. This was repeated. The flask was evacuated a third time and hydrogen was introduced by way of a filled balloon on the three-way valve. The flask was evacuated again and the hydrogen flushed in and the balloon was allowed to remain in an open position on the valve. After stirring at room temperature for 16 hours, the reaction was evacuated and flushed with nitrogen three times successively. The nitrogen filled flask was opened and the contents were vacuum filtered through MeOH wetted Celite™ maintaining a brisk flush of nitrogen over the funnel and the bed was rinsed with MeOH ( 100 ml) never allowing the bed to dry. The filtrate was concentrated under reduced pressure and then evaporated twice from toluene to give the HCl salt of compound 32-2. This salt was partitioned between DCM and saturated sodium bicarbonate solution. The organics were dried over MgSO4, filtered and concentrated under reduced pressure to give the free base of 32-2 which was used without further purification. LRMS (M+l) = 373.0
Step 3. (5J?,75)-l-(3-fluorophenyl)-8-(3-furylmethyl)-7-methyl-3-[(5-methylisoxazol-3- yI)methyl]-2,4-dioxo-l,3-diaza-8-azoniaspiro[4.51decane trifluoroaeetate Example 32
To a solution of (55,7-S)-l-(3-fluorophenyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-l,3,8- triazaspiro[4.5]decane-254-dione 32-B (0.1 g, 0.27 mmol) in DCE (2 ml) was added 3- furaldehyde (0.026 g, 0.27 mmol) followed by triacetoxyborohydride resin 2.17 gm/mmol (0.37 g, 0.8 mmol). The mixture was stirred vigorously under nitrogen for 16 hrs. The reaction was filtered through a glass fiber filter and the filtrate was rinsed with DCE and the filtrate was concentrated under reduced pressure. The residue was dissolved in 2 ml of DMSO and purified by preparative reverse phase HPLC. The desired fractions were concentrated under reduced pressure to give Example 32 as a solid. LRMS (M+l) = 453.2
1HNMR (400 MHz5 CD3OD): δ 7.57 (s, 2H), 7.42 (dd, J=6.8 Hz, IH), 7.25 (dd, J=I.8, 9.2 Hz, IH)5 7.22 (d, J=7.9 Hz, 2H), 6.27 (s, IH)5 6.16 (s, IH)3 4.78 (s, 2H)5 4.37 (d, J=14.6 Hz5 IH), 4.1 1 (d, J=14.3 Hz5 IH), 3.38 (d, J=10.4 Hz, IH)5 2.78 (bs, IH)5 2.55 (m5 4H), 2.41 (s, 3H)5 2.30 (m5 IH)5 1.46 (d, J=5.9 Hz5 3H). The following examples were prepared using a procedure similar to that described for Example 32. In some instances, the compound was isolated as the TFA salt after chromatography, and in some cases the compound was then isolated as the free base by extraction from a suitable aqueous base like bicarbonate solution with a suitable organic solvent like methylene chloride. The free base could then be transformed to the hydrochloride salt by treatment with an ether solution of HCl.
EXAMPLE 33
5R,7S)-8-benzyl-3-{[5-(3,4-dichlorophenyl)isoxazol-3-yl]methyl}-l-(3-fluorophenyl)-7-methyl- l,3,8-triazaspiro[4.5]decane-2,4-dione
Example 16
Example 33
Step 1. (5i?57-S)-l-(3-fluorophenyl)-7-methyl-l53s8-triazaspiro[4.5]decane-2,4-dione 33-A
To a solution of (7S)-I -(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l, 3,8- triazaspiro[4.5]decane-2,4-dione (Example 16. ( 5.0 g, 11.75 mmol) in MeOH (75 ml) under nitrogen was added palladium hydroxide 20 wt % on carbon (0.825 g, 1.75 mmol) and the flask was fitted with a three-way valve. The flask was evacuated with high vacuum until the solvent bubbled then nitrogen was flushed in. This was repeated. The flask was evacuated a third time and hydrogen was introduced by way of a filled balloon on the three-way valve. The flask was evacuated again and the hydrogen flushed in and the balloon was allowed to remain in an open position on the valve. After stirring at room temperature for 16 hours, the reaction was evacuated and flushed with nitrogen three times successively. The nitrogen filled flask was opened and the contents were vacuum filtered through methanol wetted Celite ™ maintaining a brisk flush of nitrogen over the funnel and the bed was rinsed with MeOH ( 100 ml), never allowing the bed to dry. The filtrate was concentrated under reduced pressure and then evaporated twice from toluene to give the desired product as a solid. LRMS (M+l) = 277.9
Step 2. (5J?,75)-8-ben2yl-l-(3-fluorophenyl)-7-methyl-l,3,8-triazaspiro[4.5]decane-2s4-dione 33- B (Alternative synthesis of Example 14. single 5R,7S enantiomer")
To a solution of (5jR,75)-l-(3-fluorophenyl)-7-methyl-l,358-triazaspiro[4.5]decane-2,4-dione 33^ A ( 0.1 g, 0.361 mmol) in DMSO (2 ml) was added benzyl chloride (0.046 g, 0.505 mmol) and triethylamine (0.101 ml, 0.72 mmol) and the reaction was allowed to stir at room temperature under nitrogen for 16 h. The reaction was filtered through a glass fiber filter and rinsed with methanol. The resulting 2.5 ml filtrate was injected into the preparative reverse phase HPLC and the desired product was eluted off using a water (0.1% TFA)/acetonitrile (0.1% TFA) gradient 95:5 to 5:95. The desired fractions were concentrated under reduced pressure to give the desired product as a solid. The residue was dissolved in DCM (5 ml) and partitioned with saturated sodium bicarbonate solution. The organic was separated and the aqueous was washed with more DCM (2ml). The combined organics were dried over Na2SO4, filtered and concentrated to give the desired product as the free base. LRMS (M+l) = 367.9
Step 3. (5Λ,7S)-8-benzyl-3- { [5-(3 ,4-dichlorophenyl)isoxazol-3-yl]methyl> - 1 -(3-fluorophenyl)-7- methyl-l,3,8-triazaspiro[4.5]decane-2,4-dione trifluoroacetate Example 33
To a solution of (5i?,7S)-8-benzyl-l-(3-fluorophenyl)-7-methyl-l,3,8-triazaspiro[4.5]decane-2,4- dione 33-B (0.037 g, 0.1 mmol) in DMSO (1 ml) under nitrogen was added 3-(chloromethyl)-5-
(3,4-dichlorophenyl)isoxazole followed by K2CO3 (0.069 g,0.5 mmol) and the reaction was stirred under nitrogen for 16 hrs. The reaction was filtered through a glass fiber filter and rinsed with MeOH. The resulting 2.5 ml filtrate was injected into the preparative reverse phase HPLC and the desired product was eluted off using a water (0.1% TFA)/acetonitrile (0.1% TFA) gradient 95:5 to 5:95. The desired fractions were concentrated under reduced pressure to give the desired product as a solid.
LRMS (M+l) = 594.4
1HNMR (400 MHz3 CD3OD): δ 8.01 (d, J=1.8 Hz, IH), 7.76 (m, IH), 7.68 (m, IH)5 7.50 (m,
IH), 7.41 (m, 2H)5 7.33 (m, IH)5 7.22 (m, 4H), 7.13 (m, IH)5 6.90 (s, IH), 4.87 (m, 2H), 4.33
(bs, 2H), 3.42 (m, IH), 2.85 (m, IH), 2.66 (d, J=10.6 Hz5 IH), 2.48 (m, 4H), 1.58 (d, J=5.3 Hz,
3H). The following examples were prepared using a procedure similar to that described for Example 33. In some instances, the compound was isolated as the TFA salt after chromatography, and in some cases the compound was then isolated as the free base by extraction from a suitable aqueous base like bicarbonate solution with a suitable organic solvent like methylene chloride. The free base could then be transformed to the hydrochloride salt by treatment with an ether solution of HCl.
EXAMPLES 34-1 AND 34-2
(δiϊ^-S^-l-CS-cyanopheny^-S-CS-isopropoxybenzyO-T-methyl-l^-dioxo-l^-diaza-S- azoniaspiro[4.5]decane trifluoroacetate (Example 34.1) and (52?,75)-l-(3-cyanophenyl)-8-(3- isopropoxybenzyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyϊ]-2,4-dioxo-13-diaza-8- azoniaspiro[4.5]decane trifluoroacetate (Example 34.2)
Step 1: Benzyl (5Λ,7iS)-l-(3-cyanophenyl)-7-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decane-8- carboxylate Intermediate 34-A
The benzyl (4Z,5i?,7»S)-l-(3-cyanophenyl)-4-immo-7-methyl-2-oxo-l ,358-triazaspiro[4.5]decane- 8-carboxylate (Intermediate VIIB was prepared in a manner similar to that described for example 11-6 in WO2007/011833 by using 3-cyanoaniline and condition A in that example. LCMS (M+!) = 418.11 To the solution of benryl (4Z55/?JS)-l-(3-cyanophenyl)-4-imino-7-methyl-2-oxo-l,3,8- triazaspiπ>[4.5]decane-8-carboxylate (intermediate VIH, 0.42 g, 1.01 mmol) in CH3CN (2.5 πiL) was added aqueous HCl (2 N, 2.5 raL) in a 48 mL sealed tube. The reaction mixture was purged with nitrogen, sealed and heated at 700C for 2 hours then 600C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the desired product. LRMS (M+l) = 418.99
Step 2: 3-[(5Λ,7S)-7-methyl-2,4-dioxo-l53,8-triazaspiro[4.5]dec-l-yl]benzonitrile 34-B
To the solution of benzyl (5i?,7S)-l-(3-cyanophenyl)-7-methyl-2,4-dioxo-l,3,8- triazaspiro[4.5]decane-8-carboxylate 34-1 (0.050 g, 0.12 mmol) in EtOH (6 mL) under nitrogen was added Pearlman's catalyst (Pd(OH)2, 20 wt % on C, 0.010 g) in a 50 mL round bottom flask. Then standard hydrogenation conditions (similar to that described in example 33) using a hydrogen filled balloon was performed at room temperature for 1 hour. The mixture was filtered through celite, and the residue was washed with MeOH (two times). The organic filtrate was concentrated under reduced pressure to give the desired product. LRMS (M+l) = 285.10
Step 3 : (5i?,75r)-l-(3-cyanophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-13-diaza-8- azoniaspiro[4.5]decane trifluoroacetate Example 34-1
The hydrogenation product 3-[(5i?,7S)-7-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]dec-l- yl]benzonitrile 34-B (0.15 g, 0.529 mmol) and l-(chloromethyl)-3-isopropoxybenzene (prepared as described in patent WO2007/011833, example 11, step 10c, 0.196 g, 1.06 mmol) were dissolved in anhydrous DMF (0.8 mL), and DIEA was added to the above solution to adjust the pH to 10. The reaction was stirred at room temperature for 2 days, and purified by reverse phase preparative HPLC to give the desired product as a TFA salt. LRMS (M+l) = 433.0
Step 4: (5/?,75)-l-(3-cyanophenyl)-8-(3-isopropoxybenzyI)-7-methyl-3-[(5-methyIisoxazol-3- yl)methyI]-2,4-dioxo-13-diaza-8-azoniaspiror4>51decane trifluoroacetateExampIe 34-2
To amixture of 3-(chloromethyl)-5-methylisoxazole (0.0217g, 0.165 mmol) and anhydrous K2CO3 ( 0.138 g, 0.247 mmol) was added a solution of 3-[(5i?,7S)-8-(3-isoρropoxybenzyl)-7- methyl-2,4-dioxo~l ,3,8-triazaspiro[4.5]dec-l-yl]benzonitrile trifluoroacetate Example 34-1 (0.045 g, 0.082 mmol) in anhydrous DMF (1 mL). After stirring at 500C for 16 hours, the reaction was quenched with aqueous NH4Cl and extracted with EtOAc (two times). The EtOAc extract was concentrated under reduced pressure. Purification by reverse phase preparative HPLC afforded the desired product as a TFA salt.
1HNMR (500 MHz, CD3OD): δ7.83 (m, IH), 7.73 (m, IH), 7.68-7.69 (m, IH), 7.51 (m,
IH), 7.31-7.35 (m, IH)5 7.06-7.07 (m, IH), 6.73-6.76 (m, 2H), 6.16 (s, IH), 4.78 (s, 2H),
4.62-4.65 (m, IH), 4.34 (d, J=13.43 Hz, IH), 4.23 (d, J=13.67 Hz, IH), 3.44 (s, IH), 2.80
(m, IH), 2.65 (m, IH), 2.26-2.54 (m, 4H)5 2.41 (s, 3H), 1.58 (d, J=5.01 Hz, 3H), 1.34 (m,
6H).
LRMS (M+l) = 528.21
The following examples were prepared using a procedure similar to that described for Example 34. hi some instances, the compound was isolated as the TFA salt after chromatography, and in some cases the compound was then isolated as the free base by extraction from a suitable aqueous base like bicarbonate solution with a suitable organic solvent like methylene chloride. The free base could then be transformed to the hydrochloride salt by treatment with an ether solution of HCl.
EXAMPLE 35
(5i?,75)-l-(3-fluoroρhenyl)-7-methyl-84(2'-methylbiphenyl-3-yl)methyl]-3-[(5-methylisoxazol- 3-yl)meihyl]-l,3,8-triazaspiro[4.5]decane-2,4-dione
Step 1. (5/?,7S)-l-(3-fluorophenyl)-8-(3-iodobenzyl)-7-methyl-l,3,8-triazaspiro[4.5]decane-2,4- dione 35-A
A solution of 1.55g (3.097 mmol) Intermediate 18-D in 3 ml 1 N HCl was stirred at 60 degrees C overnight. The solution was made basic with 6 N NaOH and extracted with dichloromethane.
The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified on silica eluting with a gradient of 0-10% MeOH in dichloromethane to give the product.
LRMS (M+l) = 493.6
Step 2. (5i?57S)-l-(3-fluorophenyl)-7-methyl-8-[(2'-methylbiphenyl-3-yl)methyl]-l33,8- triazaspiro[4.5]decane-2,4-dione 35-B
(5JR,75)-l-(3-fluorophenyl)-8-(3-iodobenzyl)-7-metliyl-l,358-triazaspiro[4.5]decane-2,4-dione (Intermediate 35-A, (950 mg, 1.92 mmole). palladium catalyst PdCl2Fe-CH2Cl2 (79 mg, 0.096 mmole), and cesium carbonate (1.88g, 5.78 mmole) and 2-tolylboronic acid (314 mg, 2.31 mmole) were measured into a 20 ml microwave vial. The vial was capped and flushed with nitrogen. A degassed mixture of 1 : 1 THF/water (6 mL) was added via syringe and the reaction was heated to 120 degrees C in the microwave for 5 minutes. The solution was transferred to a separatory funnel, diluted with water and extracted with ethyl acetate and dichloromethane. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified on silica eluting with a gradient of 0-100% ethyl acetate/ hexanes to give the product. LRMS (M+l) = 457.9
Step 3. (5i?,75)-l-(3-fluorophenyl)-7-methyl-8-[(2'-methylbiphenyl-3-yl)methyl]-3-[(5- methylisoxazol-3-yl)methyI]-l ,3,8-triazaspiro[4.5]decane-2,4-dione Example 35
hi a manner similar to that described for Example 32. (5/?,7S)-l-(3-fluorophenyl)-7-methyl-8-
[(2'-methylbiphenyl-3-yl)methyl]-l,3.8-triazaspiro[4.5]decane-2,4-dione was treated with 3-
(chloromethyl)-5-methylisoxazole and potassium carbonate in DMF at room temperature to give the desired product.
LRMS (M+l) = 553.0
The product was treated with 2 M HCl in ether to give the hydrochloride salt.
HRMS (M+l) = 553.2643 (measured), 553.2610 (calculated).
The following abbreviations are used throughout the text:
Me: methyl
Et: ethyl t-Bu: tert-bvLtyl
Ax: aryl
Ph: phenyl
Bn: benzyl
Ac: acetyl
TMSCN: trimethylsilyl cyanide
DMSO: dimethylsulfoxide
EDTA: ethylene diamine tetraacetic acid
Boc: tert-butyloxy carbonyl
CHAPS: 3-[(3-cholamidoρropyl)dimethylammonio]-2-hydroxy-l-propanesulfonate
BSA: bovine serum albumin
TFA: trifluoracetic acid
DME : dimethoxyethane
DPPA : diphenylphosphorlyazide
DCE : dichloroethane
DCM : dichloromethane THF : tetrahydrofuran BOP: benzoMazolyl-N-oxy-1xis(dimeώylamino)phosphonium hexaflurophosphate DMF: dimethylformamide DIBAL: diisobutylaluminum hydride h: hour min: minutes rt: room temperature aq: aqueous
HPLC: high performance liquid chromatography MS: mass spectrometry
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. It is intended, therefore, that the invention be defined by the scope of the claims that follow and that such claims be interpreted as broadly as is reasonable.

Claims

WHAT IS CLAIMED IS:
1. A compound of formula (I):
wherein
X is selected from the group consisting of (1) N-R5, (2) O3 and (3) S5 and R5 is selected from the group consisting of
(a) hydrogen,
(b) -Ci-io alkyl,
(c) -C2-lθ alkenyl,
(d) -C3-I2 cycloalkyl,
(e) — Co-6 alkyl-aryl, and
(f) -Cθ-6 alkyl-heteroaryl, wherein said alkyl, alkenyl, cycloalkyl, aryl and heteroaryl R5 moiety is optionally substituted with one or more
(i) aiyl, . " . .
(ii) heteroaryl, (iii) halogen,
(iv) -Cl-IO alkyl,
(v) -OC l-io alkyl,
(vi) -C3-I2 cycloalkyl,
(vii) -NC(=O)-R6,
(viii) -C(=O)NR6R6',
(ix) -C(=O)-OR6,
(X) -C(=O)-R6,
(xi) -CN
(xii) -NR6R6', wherein said aryl, akly, cycloalkyl and heteroaryl moiety is optionally substituted with one or more
(I) halogen,
(H) -Ci-6 alkyl,
(HI) -OCi-6 alkyl,
RlA and RlB are each hydrogen, provided that when X is NR.5, then RlA and RlB may together form =O;
R2 is selected from the group consisting of (1) hydrogen, (2) -Ci-I O alkyl, (3) -C2-10 alkenyl, (4) -C2-10 alkynyl,
(5) -C3-I2 cycloalkyl,
(6) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen,
(7) aryl, and
(8) heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic group, alkenyl, alkynyl, aryl or heteroaryl R2 moiety is optionally substituted with one or more
(a) halo,
(b) -OH,
(c) -CN,
(d) -Ci_io alkyl,
(e) -C2- 10 alkenyl,
(f) -C2- 10 alkynyl,
(g) -C3.12 cycloalkyl,
(h) -O-Ci_i0 alkyl,
(i) -Cθ-6 alkyl-aryl, or
(j) -Cθ-6 alkyl-heteroaryl, wherein said alkyl, alkenyl, alkynyl, aryl and heteroaryl moiety is optionally substituted with one or more
(i) halo,
(U)-OH,
(iii) -CN,
(iv) -Ci-6 alkyl, (v) -C2-6 alkenyl, (vi) -OCi -6 alkyl, (vii) -C 1-6 haloalkyl, (viii) -SO2Ci_3 alkyl,
(x) -CO2R6,
(xii) - CONRθRδ';
(xiii) -NC(=0)-Cθ-3 alkyl-NR6R6' ;
(xiv) -NC(=O)R6
(xv) -NR6R6', and
(xvi) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen;
Q is — C i-6 alkylene, wherein said alkylene is optionally substituted with one or more: (a) halo, (b) -OH,
(c) -CN,
(d) -Ci-io aikyl
(e) -C3- 12 cycloalkyl,
(f) -O-Ci-i0 alkyl,
(g) aryl, and
(h) heteroaryl;
R3 is selected from the group consisting of
(1) hydrogen,
(2) -Ci-io alkyl,
(3) -C2-IO alkenyl, (4) -C2-10 alkynyl,
(5) -C3.12 cycloalkyl,
(6) — C3-12 cycloalkenyl,
(7) aryl, and
(8) heteroaryl, wherein said alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl or aryl or heteroaryl R3 moiety is optionally substituted with one or more
(a) halo,
(b) -OH, (c) -CN,
(d) -Ci-io alkyl,
(e) -C2- 10 alkenyl,
(f) -C3-12 cycloalkyl,
(g) -O-C3-12 cycloalkyl, (h) -O-Ci_i0 alkyl,
(i) -O-C3-12 heterocyclic, wherein said heterocyclic group has from 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen, sulfur and oxygen,
0) aryl,
(k) heteroaryl,
(1) -NR6R6\ and said alkyl, cycloalkyl, aryl and heteroaryl moiety is optionally substituted with one or more
(i) halo,
(U)-OH5
(iii) -CN,
(iv) -Ci-io alkyl,
(V) -OCi-IO alkyl, and
(VI) - NR6R6'
(vii) -C2-6 alkenyl,
(viii) -C 1-6 haloalkyl,
(ix) -SO2C 1-3 alky],
(xi) -CONR6R6,
(xii) — NR5COR5', wherein R5' is selected from the same group as R5, or
(xiii) - NR7SO2R6, wherein R7 is selected from the group consisting of
(A) hydrogen
(B) -Ci-io alkyl, and
(C) -C3 -4 alkenyl;
R4 is selected from the group consisting of (1) hydrogen, (2) -Ci-10 alkyl, and
(3) -C3-4 alkenyl, wherein said alkyl or alkenyl R4 group is optionally substituted with one or more (a) halo, (b) -OH (c) -Ci-6 alkyl,
(d) -CN, (e) -O-Ci-lo alkyl.
(f) — NR8R95 wherein R.8 and R9 are^ selected from the group consisting of
(i) hydrogen, and (ii) -Ci-6 alkyl,
(g) -S(O)n-C 1-6 alkyl, wherein n is 0, 1 or 2,
(h) — C(=O)— I??, wherein R7 is selected from the group consisting of (i) hydrogen,
(ϋ) OH,
(iii) -C i_6 alkyl, and
(iv) -OC 1-6 alkyl, and
(v) aryl;
R6 and R^' are selected from the group consisting of (1) hydrogen, (2) -Ci-6 alkyl, (3) -C3-7 cycloalkyl,
(4) -Cl-6 haloalkyl,
(5) -Co-6 alkyl-aryU
(6) -Co-6alkyl-heteroaryl5
(7) halo, and
(8) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen, wherein said aryl or heteroaryl R5 moiety is optionally substituted with one or more (a) halo, (b) -Ci_6 alkyl,
(c) -O-Ci-6 alkyl, and
(d) -NO2; and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.
2. A compound of claim 1 , wherein X is NR5.
3. A compound of claim 1 or 2, wherein R.2 is phenyl, wherein the phenyl is optionally substituted with one or more
(i) halo,
(U) -OH,
(Ui) -CN5
(iv) - Ci-IO alkyl, and
(v) phenyl optionally substituted with (A) halo, (B)-OH, (C) -CN,
(D) -Ci-6 alkyl,
(E) -OCi_6 alkyl,
(F) - SO2C1-3 alkyl,
(H) -NR5SO2Ci-3alkyl, (I) - CO2R5, and (J) - CONR5R5\
4. A compound of any of claims 1 to 3, wherein Q is Ci .3 alkylene and R3 is phenyl, wherein the phenyl is optionally substituted with one or more
(A) halo,
(B)-OH,
(C) -CN,
(D) -Ci-io alkyl,
(E) -OCl-IO alkyl* and
(F) phenyl, optionally substituted with
(i) -Ci_6 alkyl, (ii) -OC 1-6 alkyl, (iii) NR5R5\
5. A compound of any of claims 1 to 4, wherein R4 is — C 1 _6 alkyl.
6. A compound of claim 1, wherein the compound of formula (I) is a compound of formula (II)
and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.
7. A compound of claim 6, wherein the compound of formula (II is a compound of formula (H"):
(I") and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.
8. A compound of any of claims 6 or 7, wherein X is NR5.
9. A compound of any of claims 6 to 8, wherein R? is phenyl, wherein the phenyl is optionally substituted with one or more
(i) halo,
(Ii) -OH,
(iii) -CN,
(iv) - Ci-io alkyl, or
(v) phenyl, optionally substituted with
(A) halo,
(B)-OH5
(C) -CN,
(D) -Ci.6 alkyl,
(E) -OCi-6 alkyl,
(F) - SO2C 1-3 alkyl, (H) -NR5SO2C1 _3alkyl, (I) -CO2R5, and
10. A compound of any of claims 6 to 10, wherein R4 is C 1 -6 alkyl.
11. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula (III)
and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.
12. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula (TV)
and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.
13. A compound of claim 1 , which is selected from the group consisting of l-(3-fluorophenyl)-8-[(2'-methylbiphenyl-3-yl)methyl]-l33,8-triazaspiro[4.5]decane-2,4-dione; 4'-fluoro-2'-[8-(34sopropoxybenzyl)-2,4-dioxo-l,3,8-triazaspiro[4.5]dec-l-yl]-N-N53- trimethylbiphenyl-4-sulfonamide; 4'-fluoro-2'-[8-(3-isopropoxybenzyl)-2,4-dioxo-l53,8-triazaspiro[4.5]dec-l-yl]-iV^V- dimethylbiphenyl-4-sulfonamide;
4'-fluoro-2'48<3-isopropoxybenzyl)-3-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]dec-l-yl]-ΛUV- dimethylbiphenyl-4-sulfonamide;
4'-fluoro-2'-[8-(3-isopropoxybenzyl)-2,4-dioxo-3-propyl-l,358-triazaspiro[4.5]dec-l-yl]-N,iV- dimethylbiphenyl-4-sulfonamide;
4'-fluoro-2'-[8-(3-isopropoxybenzyl)-2,4-dioxo-l,3,8-triazaspiro[4.5]dec-l-yl]-iV^V- dimethylbiphenyl-4-sulfonamide;
2l-(8-benzyl-2,4-dioxo-l,358-triazaspiro[4.5]dec-l-yl)-4'-fluoro-iVJV-dimethylbiphenyl-4- sulfonamide;
4'-fluoro-2'-[8-(3-isopropoxybenzyl)-2,4-dioxo-l,3,8-triazaspiro[4.5]dec-l-yl]-NJΛr,3- trimethylbiphenyl-4-carboxamide;
5 - {4-fluoro-2- [8 -(3 -isopropoxybenzyl)-2 ,4-dioxo- 1 ,3 ,8-triazaspiro [4.5] dec- 1 -yljphenyl } -NJ^- dimethylthiophene-2-sulfonamide;
(5i?,7S)-8-benzyl-l-(2-bromo-5-fluorophenyl)-7-methyl-l53,8-triazaspiro[4.5]decane-254-dione;
(5i?,7S)-l-(2-bromo-5-fluorophenyl)-8-{3-isoproρoxybenzyl)-7-methyl-l,3,8- triazaspiro[4.5]decane-2,4-dione;
(5i?,7<S)-(5S,7R)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3,8- triazaspiro[4.5]decane-2,4-dione; l-(2-bromo-5-fluorophenyl)-8-(3-isopropoxybenzyl)-l,358-triazaspiro[4.5]decane-2,4-dione;
(SΛJ^-CSSJRVδ-benzyl-l-CS-fluorophenyl^-methyl-l^.S-triazaspiroμ.SJdecane^^-dione;
N-(3 - {4-fluoro-2-[8-(3 -isopropoxyben2yl)-2,4-dioxo- 1 ,3 ,8-triazaspiro [4.5]dec- 1 -yljphenyl }prop-
2-yn- 1 -yl)-N-methylmethanesulfonamide;
(5i?,75)-l-(3-fluorophenyl)-8-(3-isopropoxybeπzyl)-7-methyl-l,3,8-triazaspiro[4.5]decane-2,4- dione;
(5i?,75)-(5S,7R)-8-benzyl-l-[4-fluoro-4'-(methylsulfonyl)biphenyl-2-yl]-7-methyl-1358- triazaspiro[4.5]decane-2.4-dione;
(5i?,75)-l-(3-fluorophenyl)-7-methyl-8-[(2'-methylbiphenyl-3-yl)rnethyl]-l,3,8- triazaspiro [4.5]decane-2 ,4-dione; l-(3-fluorophenyl)-8-[(2I-me%lbiphenyl-3-yl)methyl]-3-(pyridϊn-2-ylrnethyl)-l;,3,8- triazaspiro[4.5]decan-2-one;
4'-fluoro-2'-[8-(3-isopropoxybenzyl)-2-oxo-lJ3,8-triazaspiro[4.5]dec-l-yl]-N>N- dimethylbiphenyl-4-sulfonamide;
4'-fluoro-2'-[8-(3-isopropoxybenzyl)-2-oxo-3-propyl-l:,3,8-tria2aspiro[4.5]dec-l-yl]-Λζ>N- dimethylbiphenyl-4-sulfonamide;
4'-fluoro-2'-[8-(3-isopropoxybenzyl)-3-methyl-2-oxo-l,358-triazaspiro[4.5]dec-l-yl]-N5N- dimethylbiphenyl-4-sulfonamide; 1 -[4-fluoro-4'-(methylsulfonyl)biphenyl-2-yl]-8-(3 - isopropoxyben2yl)-l53,8-triazaspiro[4.5]decaB-2-one;(5/?.7S)-(5S,7R)-8-ben2yl-l-(3- fluorophenyO-T-methyl-l^^-triazaspiro^.SJdecan-l-onejCSiϊJi-O-CSSjT^-l-CS-fluorophenyl)-?- methyl-8-(3-{[(li?)-l-methylpropyl]oxy}ben2yl)-3-pent-4-en-l-yl-l,3,8-triazaspiro[4.5]decan-2- one^SΛJ^-l^S-fluoropheny^-δ-IS^ClΛ^-methoxy-l-methylethoxylbenzy^-y-methyl-l^^- triazaspiro[4.5]decan-2-one;
(5RJS)-(5S,7R)-8-benzyl-l-[4-fluoro-4t-(methylsulfonyl)-l,l'-biphenyl-2-yl]-7-methyl-l,358- triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-7-methyl-8-[(2'-methylbiphenyl-3-yl)methyl]-l;>3,8- triazaspiro[4.5]decane-2,4-dione;
1 -(3-fluoroρhenyl)-8-[(2'-methylbiphenyl-3-yl)methyl]-3-(ρyridin-2-ylinethyl)-l ,3,8- triazaspiro[4.5] decan-2-one;
(5i?,7S)-8-benzyl-l-(3-fluorophenyl)-7-methyl-3-oxa-l,8-dϊazaspiro[4.5]decan-2-one; (5i?,7S)-l-
(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-[2-(4-methoxyphenyl)ethyl]-7-methyl-l5358- triazaspiro[4.5]decane-2,4-dione;
(5R97S)-3-(cyclohexylmethyl)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3,8- triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-(3-methoxybenzyl)-7-methyl-l,3,8- triazasρiro[4.5]decane-2,4-dione;
N-{2-[(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-l,3,8- triazaspiro[4.5]dec-3 -yl]ethyl }benzamide;
(5RJS)- 1 -(3-fluorophenyl)-8-(3-isopropoxyben2yl)-7-methyl-3 -[(1 -methyl- 1 H-1 ,2,4-triazol-3- yl)methyl]-l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)- 1 -(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3 -[2-( 1 H-pyrazol- 1 -yl)ethyl]- l,358-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(5-methyl-l,2s4-oxadiazol-3- y l)methy 1] - 1 ,3 , 8-triazaspiro [4.5]decane-2,4-dione;
(5R,7S)-3-(2-fluoroethyl)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3,8- triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-3-(l ,2-benzi soxazol-3 -ylmethyl)- 1 -(3-fluorophenyl)-8-(3 -isopropoxybenzyl)-7-methyl-
1,3, 8-triazaspiro [4.5] decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-3-[2-(2-fluorophenyl)-2-oxoethyl]-8-(3-isopropoxyben2yl)-7-methyl-
1.3,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-3-[(l-benzyl-lH-l,2,4-triazol-5-yl)methyl]-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-
7-methyl-l ,3 ,8-triazaspiro[4.5]decane-2,4-dione;
(5R57S)-l-(3-fluorophenyl)-3-(lH-imidazol-2-ylmethyl)-8-(3-isopropoxybenzyl)-7-methyl-1.358- triazaspiro[4.5]decane-2,4-dione; (5R57S)-3-{[5-(4-chlorophenyl)-l53-oxazol-2-yl]methyl}-l-(3-fluorophenyl)-8-(3- isopropoxybenzyl)-7-methyl-l,3,8-triazaspiro[4.5]decane-2.4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(3-ρhenyl-l,2,4-oxadiazol-5- yl)methyl]-l,3,8-triazaspiro[4.5]decane-2.4-dione;
(5R,7S)-3-[(5-cyclopropyl- 1 ,354-thiadiazol-2-yl)methyl]-l -(3-fluorophenyl)-8-(3- isopropoxybenzyl)-7-methyl-l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7 S)- 1 -(3 -fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3 - [(5 -methylisoxazol-3 - yl)methyl]-l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(2-methyl-l,3-thiazol-4- yl)methyl]-l5338-triazaspiro[4.5]decane-2,4-dione-
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-{[5-(4-methoxyphenyl)-l,2,4-oxadiazol-3- yl]methyl}-7-methyl-l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-3-[(l,3-dimethyl-lH-pyrazol-5-yl)methyl]-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7- methyl- 1 ,3 , 8 -triazaspiro [4.5]decane-2,4-dione ;
(5R,7 S)- 1 -(3-fluorophenyl)- 8-(3 -isopropoxybenzyl)-7-methyl-3 - [(5 -phenylisoxazol-3 -yl)methyl] - l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-3-{[5-(3,4-dichlorophenyl)isoxazol-3-yl]methyl}-l-(3-fluorophenyl)-8-(3- isopropoxybenzyl)-7-methyl-l,3.8-triazaspiro[4.5]decane-2.4-dione;
3-[(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-l,3,8- triazaspiro[4.5]dec-3-yl]propanoic acid;
[(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-l,3.8- triazaspiro[4.5]dec-3-yl]acetic acid;
N-(4-chlorophenyl)-2-[(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo- l,3,8-triazaspiro[4.5]dec-3-yl]acetamide;
(5RS7S)- 1 -(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-raethyl-3-(l ,2,4-oxadiazol-3-ylmethyl)- l,338-triazaspiro[4.5]decane-2,4-dione;
(5RJS)-l-(3-fluorophenyl)-8-(3-isopropoxyben2yl)-7-methyl-3-(pyridin-2-ylmethyl)-l,3,8- triazaspiro[4.5]decane-2,4-dione;
(SΛJ^-l-CS-fluoropheny^-S-CS-furylmethy^-S-CS-isopropoxybenzyO^-methyl-l^.S- triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-(isoxazol-3-ylraethyl)-7-methyl-l53,8- triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-(l,3-oxazol-2-ylmethyl)-l,338- triazaspiro[4.5]decane-2,4-dione;
(5R.7S)-l-(3-fluorophenyl)-8-(3-isoproρoxybenzyl)-7-methyl-3-[(3-methyl-l,2,4-oxadiazol-5- yl)methyl]-l,3,8-triazaspiro[4.5]decane-2,4-dione; (5R,7S)-3-[(3-ethyl-l,2,4-oxadiazol-5-yl)methyl]-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7- methyl-l,3»8-triazaspiro[4.5]decane-2>4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-(isoxazol-5-ylmethyl)-7-methyl-l,3,8- triazaspiro [4.5] decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(l-methyl-lH-l,2.4-ixiazol-5- yl)methyl]-l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)- 1 -(3 -fluorophenyl)-8-(3 -isopropoxyben2yl)-7-methyl-3-[( 1 -methyl- 1 H-ϊmidazol-2- yl)methyl]-l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)- 1 -(3-fluorophenyl)-8-(3 -isopropoxybenzyl)-7-rnethyl-3 -[( 1 -phenyl- IH-152,3-triazol-4- yl)methyl]-l,358-triazaspiro[4.5]decane-2l)4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-(pyrazin-2-ylmethyl)-l,3,8- triazaspiro [4.5] decane-2,4-dione;
(5R,7S)-3-tert-butyl-l-(3-fluorophenyl)-8-(3-isopiOpoxybenzyl)-7-methyl-l,3,8- triazaspiro [4.5] decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-(l-methyl-l-phenylethyl)-l,3,8- triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-(l,3-thiazol-2-ylmethyl)-l,3,8- triazaspiro [4.5] decane-2,4-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-(l,3-thiazol-4-ylmethyl)-l,3,8- triazaspiro[4.5]decane-254-dione;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-(2-methoxy-l,l-dimethylethyl)-7-methyl- l,358-triazaspiro[4.5]decane-2,4-dione;
(5R,7S)- 1 -(3-fluorophenyl)-3 -(2-furylmethyl)-8-(3 -isopropoxybenzyl)-7-methyl- 1 ,3 ,8- triazaspiro[4.5]decane-2,4-dione;
(5i?,7iS)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-3-phenyl-l,3-diaza-8- azoniaspiro[4.5]decane;
(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-phenyl-l,3,8- triazaspiro[4.5]decane-2;,4-dione;
(5R,7S)-l,3-bis(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3,8-triazaspiro[4.5]decane-
2,4-dione;
3-[(5R,7S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-l,3,8- triazaspiro[4.5]dec-3-yl]benzonitrile;
(5R57S)-3-[3-(dimethylamino)phenyl]-l-(3-fluorophenyl)-8-(3-isopropoxyben2yl)-7-methyl- l,3,8-triazaspiro[4.5]decane-2J4-dione;
(5R,7S)-l-(3-fluorophenyl)-3-(lH-indol-5-yl)-8-(3 -isopropoxybenzyl)-7-methyl-l5358- triazaspiro[4.5]decane-2,4-dione; 3-[(5R57S)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-l,3,8- triazaspiro[4.5]dec-3-yl]benzoic acid;
(5i?,7S> 1 -(S-fluoropheπyO-S-CS-fiirylmethyO-T-methyl-S-tCS-methylisoxazol-S-y^methyl]- 1 ,3 ,8- triazaspiro[4.5]decane-2,4-dione;
N-[4-({(5R,7S)-l-(3-fluorophenyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-2.4-dioxo-l53,8- triazaspiro[4.5]dec-8-yl}methyl)phenyl]acetamide;
(5RJS)-l-(3-fluorophenyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-8-(pyridin-3-ylmethyl)- l,3,8-triazaspiro[4.5]decane-2,4-dione;
(5R57S)-8-benzyl-l -(3-fluoroρhenyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]- 1 ,3 ,8- triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-8-(2-fluorobenzyl)-l-(3-fluorophenyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]- l,3>8-triazaspiro[4.5]decane-254-dione;
(5R.7S)-8-(cyclobutylmethyl)-l-(3-fluorophenyl)-7-niethyl-3-[(5-methylisoxazol-3-yl)methyl]- l,358-triazaspiro[4.5]decane-234-dione;
(5R.7S)-8-benzyl-3-{[5-(3,4-dichlorophenyl)isoxazol-3-yl]methyl}-l-(3-fluorophenyl)-7-methyl- l,3,8-triazaspiro[4.5]decane-2,4-dione;
N-(4-{[(5R,7S)-l-(3-fluorophenyl)-7-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]dec-8- yl]methyl}phenyl)acetamide;
(5R.7S)-3-{[5-(354-dichlorophenyl)isoxazol-3-yl]methyl}-8-(2-fluorobenzyl)-l-(3-fluorophenyl)-
7-methyl- 1 ,3 ,8 -triazaspiro[4.5]decane-2,4-dione;
(5R,7S)-8-(cyclobutylmethyl)-3- { [5-(3 ,4-dichlorophenyl)isoxazol-3-yl]methyl} -1 -(3- fluorophenyl)-7-methyl- 1 ,3 ,8-triazaspiro[4.5]decane-2,4-dione;
3-[(5/?,7>S)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]dec-l- yl]benzonitrile;
3-{(5i?^5)-8-(3-isopropoxybenzyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-2>4-dioxo-l,3,8- triazaspiro[4.5]dec-l-yl}benzonitrile;
3-[(5R,7S)-3-[(5-cyclopropyl-l,3,4-thiadiazol-2-yl)methyl]-8-(3-isopropoxybenzyl)-7-methyl-
2,4-dioxo-l,3j8-triazaspiro[4.5]dec-l-yl]benzonitrile;
3-[(5R,7S)-3-{[5-(354-dichlorophenyl)isoxazol-3-yl]methyl}-8-(3-isopropoxyben2yl)-7-methyl-
2,4-dioxo- 1 ,3 ,8-triazaspiro [4.5]dec- 1 -yl]benzonitrile;
3-{(5R,7S)-8-(3-isopropoxyben2yl)-7-methyl-254-dioxo-3-[(l-phenyl-lH-l,253-triazol-4- yl)methyl]-l,35.8-triazaspiro[4.5]dec-l-yl}benzonitrile;
3-{(5R,7S)-8-(3-isopropoxybenzyl)-3-[2-(4-methoxyphenyl)ethyl]-7-methyl-2,4-dioxo-l,338- triazaspiro[4.5]dec-l-yl}benzonitrile;
N- {2-[(5R,7S)-l -(3-cyanophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo- 1,3,S- triazaspiro[4.5]dec-3-yl]ethyl}benzamide; 3 -((5R,7S)-8-(3-isopropoxybenzyl)-3 - { [5-(4-methoxyphenyl)isoxazol-3 -yl]methyl } -7-methyl- 2,4-dioxo-l,3j8-triazaspiro[4.5]dec-l-yl)benzonitrile; and
(5i?,7-S)-l-(3-fluorophenyl)-7-me%l-8-[(2'-methylbiρhenyl-3-yl)methyl]-3-[(5-methylisoxazol- 3-yl)methyl]-l,3,8-triazaspiro[4.5]decane-2,4-dione;
and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.
14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
15. A method of treating Alzheimer's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16. A method for the manufacture of a medicament for inhibiting β-secretase en2yme activity in mammals, comprising combining a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
EP07811660A 2006-09-07 2007-09-04 Spiropiperidine beta-secretase inhibitors for the treatment of alzheimer's disease Withdrawn EP2063889A4 (en)

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